alkenes to an Oxyallyl Cation - ACS Publications - American Chemical

Jun 2, 2015 - the alkene was positioned over the cyclic oxyallyl cation, and the relative ... oxyallyl cation.1−5 In a classical Nazarov reaction, d...
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Density Functional Theory Study of BF3‑Mediated Additions of Enols and [(Trimethylsilyl)oxy]alkenes to an Oxyallyl Cation: Homologous Mukaiyama Reactions Luc M. LeBlanc, Russell J. Boyd,* and D. Jean Burnell* Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia B3H 4R2, Canada S Supporting Information *

ABSTRACT: The addition of enols and [(trimethylsilyl)oxy]alkenes, bearing methyl substituents at various positions, to a cyclic, BF3-complexed oxyallyl cation has been studied at the M06/6-311G(d)//B3LYP/6-31G(d) level of theory. The reactions with the [(trimethylsilyl)oxy]alkenes are homologous Mukaiyama reactions, which have not been examined computationally previously. In most instances a number of transition states were located, and the difference in energy between these transition states was not large, which pointed to low levels of diastereoselectivity in the reactions of the oxyallyl cation model compound. The lowest energy transition states were those with a synclinal geometry in which the alkene was positioned over the cyclic oxyallyl cation, and the relative orientation of the alkene and the oxyallyl cation was rationalized in terms of stabilizing intermolecular interactions, revealed by NBO analysis, between one or more fluorines of the complexed BF3 and hydrogens on the alkene moiety, and between the oxygen on the alkene and the π-system of the oxyallyl cation. Because, in most instances with these simple models, two or more transition states of relatively low energy were located, predictions of diastereoselectivity in more complex examples that are based on simple models cannot be recommended.

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INTRODUCTION The Lewis-acid-mediated Nazarov reaction proceeds via a cyclic oxyallyl cation.1−5 In a classical Nazarov reaction, deprotonation leads to the formation of a cyclopentenone, but more recent developments have shown that the oxyallyl cation can be intercepted by nucleophiles in “interrupted” Nazarov reactions to yield substituted cyclopentanone derivatives.6 The nucleophiles have included oxygen-substituted alkenes. In the first example (Scheme 1), a BF3-mediated Nazarov reaction generated the oxyallyl cation 1, which was intercepted by the enol ether 2 to give the dicarbonyl compound 3 in racemic form in 86% yield after aqueous workup.7 In a similar way the oxyallyl cation 4 was intercepted by the silyloxyalkene 5 to provide racemic 6 in 81% yield.8 What is most intriguing about these reactions is the level of diastereoselectivity in some instances. Compound 3 was obtained as a 9:1 mixture (epimeric at the carbon shown with *); the predominant isomer is shown in Scheme 1. Compound 6 was obtained as a single diastereomer, but in contrast, when the oxyallyl cation 7 was intercepted by the silyloxyalkene 5, the racemic product 8 was a 3:2 mixture of epimers in a yield of 83%.8 The addition of the oxygen-substituted alkenes onto the oxyallyl cation is highly reminiscent of the Lewis-acid-mediated Mukaiyama aldol reaction.9−13 Indeed, the reactions shown in Scheme 1 have been described as homologous Mukaiyama reactions.8 The Mukaiyama aldol reaction is a cross-aldol process in which a silyloxyalkene attacks an aldehyde, ketone or acetal. A Lewis acid serves to activate the carbonyl, and the reaction delivers a β-hydroxycarbonyl compound.9−13 Further © 2015 American Chemical Society

Scheme 1. Additions of Oxygen-Substituted Alkenes to the Cyclic Oxyallyl Cations Generated by Nazarov Reactionsa

a

TBS = (tert-butyldimethyl)silyl.

development of the Mukaiyama aldol reaction has led to the formation of compounds with a high degree of optical purity, and applications of the reaction in synthetic organic chemistry are now numerous.14,15 Received: March 29, 2015 Revised: May 30, 2015 Published: June 2, 2015 6714

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The Journal of Physical Chemistry A A reasonable starting point for the computational examination of diastereoselectivity in the addition of oxygen-substituted alkenes to cyclic oxyallyl cations is consideration of the mechanism of the Lewis-acid-mediated Mukaiyama aldol reaction. In the initial reports, TiCl4 was employed as the Lewis acid, and a cyclic, “closed” transition state was postulated (Scheme 2). Chelation-control was used to rationalize the

In spite of the synthetic importance of the Lewis-acidmediated Mukaiyama reaction, there have been surprisingly few computational studies of this reaction. Wong and Wong22 explored various pathways for the reaction of the simplest substrates, [(trihydrosilyl)oxy]ethene with formaldehyde, in the presence of TiCl4 and other metal chlorides. The lowest energy pathway (MP2/6-311+G(d,p)//B3LYP/6-31G(d)) was via a concerted, six-membered transition state in which chlorine was transferred from the carbonyl-complexed TiCl4 to the alkene at the same time as the new carbon−carbon bond formed. I2mediated reactions of the same substrates were also proposed to involve a cyclic transition state, but when 1-phenyl-1[(trimethylsilyl)oxy]ethene and benzaldehyde were employed, the lowest energy pathway was acyclic.23 The crucial issue of the diastereoselectivity of Lewis-acid-mediated Mukaiyama aldol reactions has been studied computationally at the M06/ 6-311G(d)//B3LYP/6-31G(d) level with the IEFPCM solvation model by Lee, Helquist, and Wiest.24 These authors used variously substituted silyloxyalkenes with acetaldehyde and benzaldehyde and with BCl3 as the Lewis acid. The important conclusions were that the open transition state geometries varied significantly from the strictly staggered arrangements that Heathcock had considered, that antiperiplanar geometries were not the lowest energy transition states with some silyloxyalkenes, and that diastereoselectivity was not predicted to be synthetically useful except when the silyloxyalkene bore a very sterically encumbering substituent such as tert-butyl. In other words, for many pairs of reactants two or more open transition states of similar energies were located. Morokuma recently computationally examined an aqueous, lanthanide Lewis-acid-catalyzed variant of the Mukaiyama reaction with an open transition state.25,26

Scheme 2. Mukaiyama Aldol Reaction Mediated by TiCl4 Illustrating the Closed, or Cyclic, Transition State and the Open Transition State

relative stereochemistry of products.9−13 However, in a systematic study of Lewis-acid-mediated reactions involving many substrate pairs, Heathcock and co-workers16 noted that the BF3-mediated reactions provided product ratios similar to those of TiCl4-mediated reactions, and because BF3 would be very unlikely to participate in chelation control, it was concluded that the transition state is acyclic, i.e, “open”. This view was consistent with some earlier observations with related systems17−19 and was supported by subsequent studies by Denmark et al.20,21 Heathcock used the relative stereochemistry of the major products as well as arguments involving the minimization of steric and dipole−dipole interactions to propose that the geometry of the lowest energy transition state is staggered with respect to the incipient carbon−carbon bond, with the carbonyl and the alkene in an antiperiplanar arrangement.16

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COMPUTATIONAL METHODS Quantum mechanical calculations were performed using the Gaussian 09 software package.27 Stationary points were fully optimized using the B3LYP density functional28−31 and the 631G(d) basis set. Minima and first-order saddle points were characterized by their number of imaginary frequencies, 0 and

Figure 1. Geometries considered for the transition states of the addition of enols 10a−13a (X = H) or [(trimethylsilyl)oxy]alkenes 10b−13b (X = TMS) to the oxyallyl cation 9. (a) Orientations A−F of the incoming enols or [(trimethylsilyl)oxy]alkenes relative to the oxyallyl cation. These orientations are approximately depicted as staggered conformations, but the values in parentheses indicate the ranges of the dihedral angle ϕ(C2′,C1′,C1,C2) that each depiction encompasses. (b) Geometry of the X substituent relative to the double bond, as described by the dihedral angle ϕ(X,O′,C2′,C1′). (c) Geometry of the complexed BF3 relative to the position of the enol or [(trimethylsilyl)oxy]alkene, as described by the dihedral angle ϕ(C3,C2,O,B). 6715

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RESULTS AND DISCUSSION The aim of the present work was to examine the mechanism of the reaction of the five-membered oxyallyl cation 9 with oxygen-substituted ethene and to explore the effects of additional substitution by methyl groups on the alkene (Scheme 3). The aim was to circumscribe the most important

1, respectively, following normal-mode vibrational analysis. Intrinsic reaction coordinate calculations32−36 were performed on first-order saddle points to identify the corresponding minima on either side, i.e., the reactant and product complexes. The magnitude of the barrier for each transition state was calculated from the energy of the associated reactant complex. Single-point energies of the optimized structures were computed at the M06/6-311G(d) level of theory,37,38 although there were no significant differences with the B3LYP/6-31G(d) energies. A comparison of the relative energies for three transition states, computed at B3LYP/6-31G(d) and at B3LYP/6-311++G(d,p), did not show significant differences either. All geometries and thermodynamic data were obtained from calculations done in the gas phase at 298.15 K and 1.0 atm. In contrast with Lee, Helquist, and Wiest,24 we used BF3 rather than BCl3 as the Lewis acid because BF3 was the Lewis acid used experimentally, but [(trimethylsilyl)oxy]alkenes, which would have been synthetically accessible, were the calculated substrates rather than the [(tert-butyldimethylsilyl)oxy]alkenes that were actually used experimentally.8 Although the reactions of enols with cyclic oxyallyl cations are not presently synthetically viable, these were also examined because the steric requirement of H versus trimethylsilyl might provide clues regarding the steric contribution to the diastereoselectivity and because calculation of the smaller system was helpful in finding transition states with the [(trimethylsilyl)oxy]alkenes. Furthermore, it was considered important to locate the various conformers of the enols and [(trimethylsilyl)oxy]alkenes as their interactions with the oxyallyl cation could undoubtedly be very different, and dismissing some conformers might result in missing some lower energy pathways. Relaxed 2D potential energy surface (PES) scans were performed by incrementing the dihedral angle about the carbon−oxygen bond by 10−20° in a 180° range with the anti and syn conformers as starting and end points for the scans. Full optimizations of the minima and of the transition states for the interconversions between these minima obtained from the critical points on this 2D PES then followed (Table S1, Supporting Information). Locating the transition states for the addition of enols and [(trimethylsilyl)oxy]alkenes to a cyclic oxyallyl cation proceeded in the following manner. First, for transition states involving enols, 3D relaxed PES scans were performed by placing the two substrates in initial arrangements, i.e., placing each minimum-energy-arranged enol and the oxyallyl cation in orientations of type A and D, with BF3 either anti or syn to the site of nucleophilic attack (Figure 1), and then by incrementing the length of the incipient carbon−carbon bond in steps of 0.2 Å from 2.0 to 2.8 Å and the dihedral angle about that bond in steps of 20° from 0° to 360°. Critical points on this 3D PES were then fully optimized to locate the transition states. For transition states incorporating [(trimethylsilyl)oxy]alkenes, 3D relaxed PES scans were not performed because the trimethylsilyl moiety often interfered with the remainder of the system resulting in unsuccessful termination of the scans. Rather, searches were carried out manually by incrementing the same geometrical parameters as before. Furthermore, starting geometries were generated from the optimized enol transition states by exchanging the hydrogen atom for a trimethylsilyl group, while taking into account the additional minima (e.g., gauche conformations in addition to the anti and syn conformations of the enols) for each of the [(trimethylsilyl)oxy]alkenes.

Scheme 3. Computationally Studied Additions of OxygenSubstituted Alkenes to an Oxyallyl Cationa

a

The oxyallyl cation is 9, 10a−13a are enols, 10b−13b are [(trimethylsilyl)oxy]alkenes, and the two possible diastereomeric products would be 14 and 15 after aqueous workup. TMS = trimethylsilyl.

geometrical and energetic features of the mechanism without the added issue of facial selectivity that would exist with the more complex oxyallyl cations in Scheme 1. The oxygensubstituted alkenes were the four enols (10a−13a) along with their corresponding [(trimethylsilyl)oxy]alkenes (10b−13b). The latter could serve as reagents in homologous Mukaiyama reactions. Transition states for the addition of the enols and the [(trimethylsilyl)oxy]alkenes to the oxyallyl cation were located considering a large number of possible geometries of approach between substrates, as shown in Figure 1. It should be noted that transition states could not be located when starting geometries for the enols had the hydroxyl hydrogen near the BF3 group. In those instances, a fluorine abstracted the hydroxyl’s hydrogen to form HF as the carbon framework collapsed immediately to the product. (A detailed discussion of this issue, which was not the focus of the present study, appears in the Supporting Information.) The analogous process in which fluorine was transferred to the silicon of the [(trimethylsilyl)oxy]alkenes prior to carbon−carbon bond formation was not observed, although desilylation by fluorine was sometimes evident after carbon−carbon bond formation. However, this process would not affect the diastereoselectivity. (The Supporting Information includes some data regarding such processes.) Thus, with the enols, a reaction pathway to the products appeared to exist that was not comparable with the [(trimethylsilyl)oxy]alkene reaction. The barriers for the transition states that were located were low (Table 1). This Table 1. Comparison of the Energy Barriers for the Transition States with the Different Alkene Types at the M06/6-311G(d)//B3LYP/6-31G(d) Level of Theory ΔG‡ (kJ mol−1)

a

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alkene

a (X = H)

b (X = TMS)

10 11 12 13

12−25 5−12 2−25 9−18

0−19 5−8 3−17 8a

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Table 2. Relative Energies and Geometrical Data for the Transition States (TSs) for the Additions of Enols 10a−13a and [(Trimethylsilyl)oxy]alkenes 10b−13b to the Oxyallyl Cation 9 at the M06/6-311G(d)//B3LYP/6-31G(d) Level of Theory TS

alkene

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

10a

11a

12a

13a

10be

11b

12b

13b

ΔE‡a (kJ mol−1)

ΔG‡b (kJ mol−1)

R(C1,C1′)c (Å)

approximate orientationd

resulting diastereomer

ϕ(C2′,C1′,C1,C2) (deg)

ϕ(X,O′,C2′,C1′) (deg)

ϕ(C3,C2,O,B) (deg)

0.0 18.7 26.8 30.4 31.9 36.9 40.1 47.8 0.0 3.3 21.6 0.0 0.7 2.5 5.9 9.1 12.5 33.1 33.9 35.6 0.0 15.0 21.2 0.0 1.4 19.9 0.0 9.8 12.0 0.0 6.3 7.8 0.0

0.0 16.9 26.6 29.4 30.0 36.0 37.1 45.1 0.0 3.5 20.1 0.0 1.3 3.1 6.3 9.2 12.8 32.7 34.0 36.7 0.0 11.4 15.7 0.0 2.4 15.0 0.0 4.3 5.5 0.0 4.5 7.1 0.0

2.545 2.472 2.369 2.177 2.152 2.235 2.355 2.179 2.386 2.434 2.322 2.389 2.243 2.367 2.326 2.182 2.329 2.138 2.287 2.175 2.311 2.214 2.119 2.308 2.344 2.261 2.411 2.405 2.468 2.411 2.272 2.439 2.277

E E C F F C D D F B C F A F B A B D C C F D A C C F C F B F A B C

15 15 14 15 15 14 15 15 15 14 14 15 14 15 14 14 14 15 14 14 15 15 14 14 14 15 14 15 14 15 14 14 14

30.4 −0.3 −64.8 −72.8 −82.0 −65.5 −179.1 160.2 −86.9 105.8 −70.5 −81.7 −176.6 −86.5 100.1 177.2 108.5 159.2 −67.1 −76.6 −64.5 176.9 158.8 −75.5 −71.5 −76.2 −90.8 −92.8 108.2 −85.6 178.6 106.4 −92.0

155.3 −7.4 −179.7 −9.0 −9.0 −175.9 177.5 176.4 −8.2 6.9 −177.4 179.6 8.1 −7.3 −177.4 −175.4 5.9 174.2 −172.7 −174.6 −11.0 174.5 −170.5 113.6 64.6 −27.3 82.9 −30.5 29.8 −159.1 160.4 171.9 87.4

153.8 166.6 171.8 −44.3 −178.6 −3.7 167.7 −42.9 −41.3 −33.7 −3.6 −41.3 −16.9 −41.9 −38.2 −18.4 −41.5 −17.6 −27.7 134.7 −32.6 −16.7 −16.3 −35.1 10.5 −43.3 −38.2 −38.7 −32.9 −37.8 −16.4 −38.7 −39.8

a

Zero-point-corrected electronic energies relative to the energy of the lowest energy transition state with that alkene. bGibbs energies relative to the energy of the lowest energy transition state with that alkene. cLength of the incipient carbon−carbon bond. dApproximate orientation of the doublebond of the enol or [(trimethylsilyl)oxy]alkene relative to the oxyallyl cation. The generalized orientations A−F are defined in Figure 1a. This orientation is precisely described by the dihedral angle ϕ(C2′,C1′,C1,C2). eGibbs energies relative to TS 24 at B3LYP/6-311++G(d,p): TS 25, 1.0 kJ mol−1; TS 26, 12.9 kJ mol−1.

was consistent with the interrupted Nazarov reactions shown in Scheme 1 taking place in 5−15 min at −78 °C.7,8 When the reaction pathways were geometrically similar, the enol substrates were generally a little less reactive than the corresponding [(trimethylsilyl)oxy]alkenes. Introduction of a methyl group at R3 of the alkene lowered the barrier for reaction, likely a result of increasing the electron density of the double bond, but methyl groups on the bonding carbon of the oxygen-substituted alkene, i.e., R1 or R2, tended to increase the barriers, presumably due to steric hindrance. More transition states were located with the enols than with the [(trimethylsilyl)oxy]alkenes. In spite of surveying a large number of starting geometries, only one transition state was found for the reaction of the [(trimethylsilyl)oxy]alkene 13b. Orientations A, B, and C in Figure 1a would lead to diastereomer 14 in Scheme 3, and orientations D, E, and F would lead to diastereomer 15. The interconversion of the reactive complexes leading to orientations A, B, and C involved very low barriers, as did, for the most part, the interconversion of the reactive complexes leading to D, E, and F.

Diastereoselectivity would arise from differences in the magnitude of the energies of the different transition states with the same alkene. Therefore, the transition state energies for the additions of the enols and [(trimethylsilyl)oxy]alkenes to the oxyallyl cation presented in Table 2 are relative to the transition state of lowest energy. Some key geometric parameters are provided also. Incipient Bond Length. The incipient bond length, R(C1,C1′) in Table 2, in the transition states varied between 2.1 and 2.6 Å, which was consistent with the computed incipient bond lengths for Mukaiyama aldol reactions.22,24 The degree of pyramidalization at C1, which was assessed from the absolute value of the dihedral angle ϕ(C1(H),C1,C5,C2), varied from 142° to 161° (i.e., 19° to 38° deviation from 180°), and the degree of pyramidalization at C1′, which was the absolute value of the dihedral angle ϕ(R1,C1′,C2′,R2), varied from 147° to 168° (i.e., 12° to 33° deviation from 180°). Although shorter incipient bond lengths did correlate with greater pyramidalization, no correlation was evident between 6717

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Figure 2. Comparison of the geometries of two transition states of the enol 12a with the oxyallyl cation 9 that differ primarily in the orientation of the O−H bond. Transition state a corresponds to TS 12 in Table 2, and transition state b corresponds to TS 14.

exception of the lowest energy transition state with enol 10a, which reacts preferentially with the BF3 moiety syn to C1, the transition states with the other enols have the H of the OH roughly coplanar with the alkene. For instance, for 11a and 13a the lowest energy transition states are roughly syn (Table 2, TSs 9 and 21), and for 12a the lowest energy transition state is almost exactly anti (Table 2, TS 12). On the contrary, in all of the transition states with the [(trimethylsilyl)oxy]alkenes, with the exception of the least favored transition state with 12b (Table 2, TS 32), the trimethylsilyl group was not close to coplanar with the alkene moiety. Earlier models proposed that an important factor in reducing the energy of a transition state was an antiparallel arrangement of larger bond moments to minimize the dipole moment.16,20,21 In an examination of the five pairs of transition states for the same alkene in Table 2 that differed mainly by the orientation of the O−X bonds, it was ascertained that for every pair the transition state with the lower dipole moment was in fact the one of lower energy, even when the differences in the barriers were small.41 To illustrate, the bond moments of the O−H and the O−BF3 bonds can be seen to be opposing in the lowerenergy transition state of TS 12 (Figure 2a) but parallel in the higher-energy transition state in TS 14 (Figure 2b). In TS 12 the dihedral angle ϕ(H,O′,C2′,C1′) was 179.6° (anti to alkene), whereas in TS 14 this dihedral angle was −7.3° (syn to alkene). Orientation of the Alkene Relative to the Oxyallyl Cation. The earlier models of the Mukaiyama aldol reaction had rationalized the diastereoselectivity in terms of a lowestenergy reaction pathway with a transition state geometry in which the orientation of the alkene relative to the carbonyl group is antiperiplanar.16,20,21 The conclusion of the recent DFT study of the Mukaiyama aldol reaction was that whereas one diastereomer tends to be formed via a transition state structure with an antiperiplanar geometry, the other diastereomer is formed primarily via a transition state structure with a synclinal geometry.24 Six staggered orientations (A−F in Figure 1a) can be postulated for the addition of an oxygen-substituted alkene to the oxyallyl cation 9. Orientations A and D could be considered to be antiperiplanar because the alkene is anti to the C1−C2 πbond. In orientations B and E, the alkene is away from the ring, and this arrangement is referred to here as synclinal-exo. In orientations C and F, referred to as synclinal-endo, the alkene is over the ring and its π-bond is parallel to the C2−C3 π-bond. Orientations A−C would lead to diastereomer 14, and orientations D−F would lead to diastereomer 15 in Scheme 3.

the incipient bond lengths, or the degrees of pyramidalization, and the energetic ordering of the transition states. Geometry of the BF3 in the Oxyallyl Cation. It might be assumed, for steric reasons, that the lowest energy transition states would have the complexed Lewis acid oriented away from the attacking alkene. On the contrary, the computed C1− C2 bond length in oxyallyl cation itself, where the complexed BF3 was anti to C1, was 1.407 Å, whereas for C2−C3 the bond length was 1.423 Å. Furthermore, the electron density at C3 was somewhat less than at C1.39 Thus, electronically, C1 appeared to be less electrophilic than C3. Therefore, the complexed BF3 was considered both away from and toward the incoming enol or [(trimethylsilyl)oxy]alkene, i.e., anti and syn to C1, and optimizations were initiated with the dihedral angle ϕ(C3,C2,O,B) initially set to both 0° and 180° (Figure 1c). The dihedral angle ϕ(C3,C2,O,B) of the lowest energy transition state with the unsubstituted enol 10a was 153.8° (Table 2, TS 1), a significant difference from 180° but still roughly a syn orientation. However, the complexed BF3 was anti (away from C1) with all other alkenes in their lowest energy transition states, although the BF3 had significantly deviated from coplanarity with the C2−C3 bond. With the [(trimethylsilyl)oxy]alkenes 10b−13b, all of the located transition states had the complexed BF3 anti (away from C1). Geometry of the Enol or [(Trimethylsilyl)oxy]alkene. The syn conformations of the enols 10a−13a (Figure 1b) were lower in energy than the corresponding anti conformations, and the anti conformation was not the lowest energy form of any [(trimethylsilyl)oxy]alkene (10b−13b). For 11b the lowest energy conformation, indeed the only minimum, was syn, obviously due to hindrance from the R3 methyl. For 12b the lowest energy conformation was gauche, which presumably minimized interactions with both methyl groups. Gauche and syn conformations were of almost equal energy for 10b, and somewhat surprisingly considering the data for 11b, for 13b the syn conformation was only 3.2 kJ mol−1 lower in energy than a gauche conformation.40 The reaction of the enol 13a was predicted (Table 2, TS 21) to react via orientation F, which would lead to diastereomer 15, whereas the corresponding [(trimethylsilyl)oxy]alkene 13b was predicted (Table 2, TS 33) to react via orientation C, which would lead to diastereomer 14. Though it might be tempting to ascribe this difference to the size of the trimethylsilyl group of 13b relative to the hydrogen of 13a, it must be emphasized that synclinal arrangements of the enols in which the enol was in the syn conformation included instances where the hydroxyl hydrogen was close to the BF3 moiety, and as noted previously, in these cases transition states could not be located. With the 6718

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Figure 3. (a) Computed geometries of the orientation C (TS 24) and the orientation F (TS 26) transition states for the reactions of [(trimethylsilyl)oxy]alkene 10b. (b) Computed geometries of the orientation C (TS 27) and the orientation F (TS 28) transition states for the reactions of [(trimethylsilyl)oxy]alkene 11b. (Diagrams to the left of the computed structures show the approximate orientations.) Important stabilizing donor−acceptor interactions are shown by the dashed lines on the computed structures.

Table 3. Summary of the NBO Analysis of Transition States of Orientations C and F for [(Trimethylsilyl)oxy]alkenes 10b and 11b stabilization energies for various intermolecular donor−acceptor interactions (kJ mol−1) alkene

orientation

TSa

F−SiCH3

O′−C3

F−C1′H

F−C2′H (or −CH3)

total stabilization (kJ mol−1)

10b

C F C F

24 26 27 28

12.6 0 12.5 0

5.0 0 1.4 0

0 1.5 8.1 4.0

0 2.6 0 11.4

30.0 7.9 28.6 18.4

11b a

The transition state (TS) in Table 2.

12b, the [(trimethylsilyl)oxy]alkenes showed a marked preference for orientation C. It is possible that orientation C would have been favored for the enols also, but in those geometries the hydroxyl would have been close to the BF3. Nevertheless, there are indications that orientation C would have been lower energy than F with the enols. For instance, comparing two transition states for 10a in which the BF3 was syn to C1 of the oxyallyl cation (i.e., the BF3 could not be near the hydroxyl) it can be seen that the orientation C in TS 3 is lower in energy than the corresponding orientation F in TS 5. With the simplest [(trimethylsilyl)oxy]alkene 10b there was a considerable difference in energy between the transition states of orientation C (TSs 24 and 25) and the transition state of orientation F (TS 26). The question is why orientation C would be of lower energy than F. Comparing TS 24 (orientation C) with TS 26 (orientation F), as in Figure 3a, using NBO analysis42 and also comparison of TS 27 (orientation C) with TS 28 (orientation F) for [(trimethylsilyl)oxy]alkene 11b, as in Figure 3b, revealed important intermolecular stabilizing interactions in the TSs, particularly in orientation C (Table 3). The first interaction was between the lone pairs on two of the fluorines of the BF3 with hydrogens of the trimethylsilyl groups. These interactions were consistent with the geometries of TSs 24 and 27. The F-to-H distances were between 2.22 and 2.33 Å, and the B−F bonds where the fluorines were involved in the F-to-H interactions were longer (1.41 Å) than the remaining B−F bond (1.37 Å).

In no instance did the lowest-energy transition state have an antiperiplanar geometry, i.e., orientation A or D. With enol 12a two transition states were almost equal in energy. The slightly higher-energy one was of orientation A (TS 13 in Table 2), but the substitution pattern of 12a and 12b may inhibit reaction via the pathway that is of lowest energy with the other substrates (see below). Synclinal-exo transition state geometries, i.e., orientations B and E, also were disfavored in every instance, with the exception of enol 10a, for which the lowest energy transition state shown in Table 2 (TS 1) was of orientation E. In this transition state, the BF3 was arranged, exceptionally, syn to the incoming alkene with a dihedral about the incipient bond, ϕ(C2′,C1′,C1,C2), of 30.4° that deviated markedly from a staggered geometry. A transition state of similar geometry was not found with 11a, which pointed to significant steric hindrance between the R3 methyl and the BF3 moiety in an E orientation. It is suspected that a number of synclinal transition state geometries with the enols were not located because, as stated above, when the hydroxyl hydrogen of an enol was set close to the BF3 group, an unwanted reaction with an extremely low energy barrier directly between the hydroxyl hydrogen and the BF3 subverted the optimization process. In spite of this shortcoming, the lowest energy transition states with enols 11a−13a and [(trimethylsilyl)oxy]alkenes 10b−13b were synclinal-endo, i.e., orientations C or F. With the exception of 6719

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transition state, TS 26, but this total stabilization was still not greater than in the orientation C transition state TS 27 for 11b. There are two important implications of the intermolecular donor−acceptor interactions. The first is that the most significant interactions are between the Lewis acid and atoms remote from the site of carbon−carbon bond formation, and so diastereomeric control of this reaction resembles a chelation controlled system, even if the degree of control is not large. The second point is that because the intermolecular interactions are mainly with the fluorines of the BF3, it is likely that the diastereoselectivity would be altered considerably if a different Lewis acid were employed. In orientation C, the R1 methyl of alkene 12b would be proximal to the oxygen of the oxyallyl cation 9, and so the lowest energy transition state with 12b is the synclinal-endo orientation F in which R1 is distal to the oxygen of 9, as shown in Figure 4a. Although no transition state could be located with 12b in orientation C, two transition states for the enol 12a were in orientation C, i.e., TSs 19 and 20, and these were at least 34 kJ mol−1 higher in energy than the transition state in orientation F. The distances from the closest hydrogen of the R1 methyl to the oxygen of the oxyallyl moiety were 2.52 Å in TS 19 and 2.66 Å in TS 20. In contrast, with alkene 13b the R2 methyl would be proximal to the oxygen of 9 in orientation F. With this alkene, the only transition state that could be located was in orientation C. Figure 4b shows this transition state with 13b. Prediction of Experimental Results. As shown in Table 2, for many oxygen-substituted alkenes there are two or more transition states for the reaction with the oxyallyl cation 9, and sometimes these are similar in energy. Thus, the overall prediction would be that diastereoselectivity would be likely to be low. Furthermore, it is unfortunate, from the point of view of extrapolation of this study to prediction, that the lowest energy transition states are those with synclinal-endo geometries. Typical substrates for Nazarov reactions are divinyl ketones substituted at one or both alkene termini. This was true for the Nazarov substrates that led to the oxyallyl cations in Scheme 1. After Nazarov cyclization, the termini became C4 and C5 of the oxyallyl cation intermediate. Modification of these positions, relative to the model oxyallyl cation 9, would have the greatest impact for synclinal-endo geometries due to steric interactions. Though it is difficult to see how oxyallyl cation 1, with the exocyclic double bond, should differ in selectivity from 9, the difference between 4 and 9 is easier to appreciate. This is because in 4 the space above the oxyallyl ring is clearly hindered by a phenyl group. The oxygenated alkene 5 is similar

Some stabilization came from F−Si interactions, but these were not as large as the F−H interactions. The F-to-Si distances were between 3.30 and 4.38 Å. (See the Supporting Information for detailed geometry information.) A second stabilizing interaction that was only seen in orientation C was between the oxygen (O′) on the alkene and the sp2 carbon of the oxyallyl cation (C3) that it subtends. This interaction was corroborated by APT analysis39 that showed that O′ was more positive in orientation C than F, although the corresponding effect at C3 was less dramatic (Table 4). The O−C interaction was weaker Table 4. APT Charges at the Oxygen on the Alkene (O′) and at the Subtended Carbon (C3) of the Oxyallyl Cation in the Transition States of Orientations C and F for [(Trimethylsilyl)oxy]alkenes 10b and 11b alkene

orientation

TSa

at O′

at C3

10b

C F C F

24 26 27 28

−1.043 −1.342 −1.066 −1.342

0.027 −0.016 0.036 0.025

11b a

The transition state (TS) in Table 2.

in TS 27 than in TS 24, but the O′-to-C3 distance was greater in TS 27 (3.30 Å versus 2.97 Å). On the contrary, in TS 27 there were significant stabilizing interactions between a fluorine and an olefinic hydrogen that were not seen with TS 24. The Fto-H distance was 2.30 Å in TS 27 versus 2.54 Å in TS 24. The NBO analysis of TS 26 in orientation F for 10b had no F−H interactions with the trimethylsilyl group and no O−C interaction between O′ and C3 as had been observed for TS 24 (orientation C). However, there were stabilizing interactions between one fluorine of the BF3 moiety and olefin hydrogens of the alkene, like in TS 27 (Figure 3c). That interacting fluorine had a B−F bond length of 1.42 Å, whereas the other two fluorines had B−F bond lengths of 1.37 and 1.39 Å. The F-to-H distances were 2.55 and 2.30 Å. The sum of the stabilizing interactions in TS 26 was much smaller than the stabilizing interactions in TS 24 in the orientation C. Transition state TS 28 in orientation F for 11b had its strongest interaction between one of the fluorines of the BF3 and a hydrogen of the R3 methyl group (Figure 3d). That F-to-H distance was only 2.18 Å, and as in the other cases, that fluorine had a longer B−F bond. The fluorine to methyl interaction was mainly responsible for the greater total intermolecular donor−acceptor stabilization energy in TS 28 relative to the other orientation F

Figure 4. Computed structures of the lowest energy transition states for the reactions of [(trimethylsilyl)oxy]alkenes 12b (a) and 13b (b) with the oxyallyl cation 9. Diagrams to the left of the computed structures show the approximate orientations. 6720

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transition states with different geometries could be located, and the energetic differences between these transition states are, for the most part, not large. Because these differences are not large, many influences could be significant in determining the diastereoselectivity of such reactions. This makes generalizations difficult, and so accurate predictions could be computationally costly because they would require consideration of the exact molecules of interest. The orientation of the reacting species was considerably influenced by stabilizing interactions between the fluorines of the Lewis acid and atoms on the [(trimethylsilyl)oxy]alkene. Thus, diastereoselectivity might be significantly altered by a change in Lewis acid.

to the computed [(trimethylsilyl)oxy]alkene 12b. The lowest energy transition state for the reaction of 12b with 9 had a synclinal-endo geometry, orientation F (TS 30 in Table 2). Orientation F would not lead to the experimental product 6, but to its undetected diastereomer. However, for oxyallyl cation 4 the energy barriers for transition states with synclinal-endo geometries would be significantly higher due to steric hindrance. The transition state for 12b next-lowest in energy in Table 2 (TS 31) was antiperiplanar, orientation A, from which the product would be the experimentally observed diastereomer 6. As different reaction pathways are available that are not vastly different in energy for the simple systems that have been studied here, modest changes in the structure of the oxyallyl cation or the oxygenated alkene may be expected to result in very significant differences in the diastereoselectivity. Product Complexes. In a preparative sense the products of these reactions, after aqueous workup, would be hydroxyketones or -aldehydes, but the immediate products would be product complexes. The structures of these product complexes depended on the geometry of the transition states by which the complexes were produced. Reactions that proceeded through antiperiplanar transition states of orientations A and D and the synclinal-endo transition state of orientation C gave the expected product complex 16 (Scheme 4). The other

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ASSOCIATED CONTENT

* Supporting Information S

Additional energy and geometrical data, Cartesian coordinates and computed energies for all computed structures, discussion and data for fluoride reactions, tables for the NBO analysis, geometrical data for some transition states, full ref 27 and additional references. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.5b03003.

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AUTHOR INFORMATION

Corresponding Authors

Scheme 4. Product Complexes Following the Reaction of Oxyallyl Cation 9 with Oxygen-Substituted Alkenes

*R. J. Boyd. E-mail: [email protected]. *D. J. Burnell. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the Natural Sciences and Engineering Research Council (NSERC). High performance computational facilities were provided by the Atlantic Computational Excellence Network (ACEnet). ACEnet is funded by the Canada Foundation for Innovation (CFI), the Atlantic Canada Opportunities Agency (ACOA), and the provinces of Newfoundland and Labrador, Nova Scotia, and New Brunswick.

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ABBREVIATIONS APT, atomic polar tensor; IEFPCM, integral equation formalism polarizable continuum model; NBO, natural bond orbital; PES, potential energy surface; TBS, tert-butyldimethylsilyl; TMS, trimethylsilyl

synclinal-endo transition state, orientation F, also led to 16 in most cases, but with two exceptions. The product complex resulting from TSs 4 and 26 (Table 2) was 17, in which fluoride had migrated from boron to carbon. This sort of process had been postulated for some Lewis-acid-mediated Mukaiyama aldol reactions of aldehydes by Wong and Wong.22 In TSs 4 and 26 the C2′ carbon of the alkene was particularly close to one of the fluorine atoms of the complexed BF3. The synclinalexo transition states, orientations B and E, went to product complex 18 in which the oxygen of the oxyallyl cation was associated with C2′ from the alkene. Such complexes were also considered by Wong and Wong,22 and Wu and West hypothesized similar ring formation in the homologous aldol reactions of alkynes with oxyallyl cations.43

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REFERENCES

(1) Review: Tius, M. A. Some New Nazarov Chemistry. Eur. J. Org. Chem. 2005, 2193−2206. (2) Review: Pellissier, H. Recent Developments in the Nazarov Process. Tetrahedron 2005, 61, 6479−6517. (3) Review: Frontier, A. J.; Collison, C. The Nazarov Cyclization in Organic Synthesis. Recent Advances. Tetrahedron 2005, 61, 7577− 7606. (4) Review: Nakanishi, W.; West, F. G. Advances in the Nazarov Cyclization. Curr. Opin. Drug Discovery Dev. 2009, 12, 732−751. (5) Review: Vaidya, T.; Eisenberg, R.; Frontier, A. J. Catalytic Nazarov Cyclization: The State of the Art. ChemCatChem 2011, 3, 1531−1548. (6) Review of “interrupted” Nazarov reactions: Grant, T. N.; Rieder, C. J.; West, F. G. Interrupting the Nazarov Reaction: Domino and Cascade Processes Utilizing Cyclopentenyl Cations. Chem. Commun. 2009, 5676−5688.

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CONCLUSIONS The reaction of an oxygen-substituted alkene with a cyclic oxyallyl cation has been studied using density functional theory. The transition state is not cyclic. In many instances a number of 6721

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The Journal of Physical Chemistry A (7) Marx, V. M.; Burnell, D. J. Nazarov Cyclizations of an Allenyl Vinyl Ketone with Interception of the Oxyallyl Cation Intermediate for the Formation of Carbon-Carbon Bonds. J. Am. Chem. Soc. 2010, 132, 1685−1689. (8) Wu, Y.-K.; McDonald, R.; West, F. G. Homologous Mukaiyama Reactions via Trapping of the Nazarov Intermediate with Silyloxyalkenes. Org. Lett. 2011, 13, 3584−3587. (9) Mukaiyama, T.; Narasaka, K.; Banno, K. New Aldol Type Reaction. Chem. Lett. 1973, 1011−1014. (10) Mukaiyama, T.; Banno, K.; Narasaka, K. New Cross-Aldol Reactions. Reactions of Silyl Enol Ethers with Carbonyl Compounds Activated by Titanium Tetrachloride. J. Am. Chem. Soc. 1974, 96, 7503−7509. (11) Banno, K.; Mukaiyama, T. New Cross Aldol Reactions. Reactions of Silyl Enol Ethers with Keto Esters Promoted by Titanium Tetrachloride. Chem. Lett. 1975, 741−744. (12) Banno, K. New Cross Aldol Reactions. Titanium TetrachloridePromoted Reactions of Silyl Enol Ethers with Carbonyl Compounds Containing a Functional Group. Bull. Chem. Soc. Jpn. 1976, 49, 2284− 2291. (13) Mukaiyama, T. Titanium Tetrachloride in Organic Synthesis. Angew. Chem., Int. Ed. Engl. 1977, 16, 817−826. (14) Review: Kan, S. B. J.; Ng, K. K.-H.; Paterson, I. The Impact of the Mukaiyama Aldol Reaction in Total Synthesis. Angew. Chem., Int. Ed. 2013, 52, 9097−9108. (15) Review: Matsuo, J.; Murakami, M. The Mukaiyama Aldol Reaction: 40 Years of Continuous Development. Angew. Chem., Int. Ed. 2013, 52, 9109−9118. (16) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. Acyclic Stereoselection. 36. Simple Diastereoselection in the Lewis Acid Mediated Reactions of Enol Silanes with Aldehydes. J. Org. Chem. 1986, 51, 3027−3037. (17) Chan, T. H.; Aida, T.; Lau, P. W. K.; Gorys, V.; Harpp, D. N. Chemistry of Enol Silyl Ethers. Part III. Stereoselection in the Condensation Between Ethyl Propionate and Aldehydes. Tetrahedron Lett. 1979, 20, 4029−4032. (18) Goasdoue, C.; Goasdoue, N.; Gaudemar, M. The Erythro- or Threo-Selective Aldol-Type Reaction via (Z)-N,N-Dimethyl-5-trimethylsilylketene S,N-Acetals. J. Organomet. Chem. 1984, 263, 273−281. (19) Dubois, J.-E.; Axiotis, G.; Bertounesque, E. Ketene Bis(trimethylsilyl) Acetals. Cross-Aldol Condensation with Aldehydes. Stereochemistry of the Reaction. Tetrahedron Lett. 1984, 25, 4655− 4658. (20) Denmark, S. E.; Henke, B. R. Investigations on Transition State Geometry in the Aldol Condensation. J. Am. Chem. Soc. 1989, 111, 8032−8034. (21) Denmark, S. E.; Lee, W. Investigations on Transition-State Geometry in the Lewis Acid- (Mukaiyama) and Fluoride-Promoted Aldol Reactions. J. Org. Chem. 1994, 59, 707−709. (22) Wong, C. T.; Wong, M. W. Mechanism of Metal ChloridePromoted Mukaiyama Aldol Reactions. J. Org. Chem. 2007, 72, 1425− 1430. (23) Wang, L.; Wong, M. W. Mechanism of Halogen-Catalyzed Mukaiyama Aldol Reactions: Concerted or Stepwise? Tetrahedron Lett. 2008, 49, 3916−3920. (24) Lee, J. M.; Helquist, P.; Wiest, O. Diastereoselectivity in LewisAcid-Catalyzed Mukaiyama Aldol Reactions: a DFT Study. J. Am. Chem. Soc. 2012, 134, 14973−14981. (25) Hatanaka, M.; Maeda, S.; Morokuma, K. Sampling of Transition States for Predicting Diastereoselectivity Using Automated Search Method − Aqueous Lanthanide-Catalyzed Mukaiyama Aldol Reaction. J. Chem. Theory Comput. 2013, 9, 2882−2886. (26) Hatanaka, M.; Morokuma, K. The Role of Water in MukaiyamaAldol Reaction Catalyzed by Lanthanide Lewis Acid: a Computational Study. J. Am. Chem. Soc. 2013, 135, 13972−13979. (27) Frisch, M. J.; et al. Gaussian 09, Revisions C.01 and D.01; Gaussian Inc.: Wallingford, CT, 2010 and 2013. See the Supporting Information for the complete reference.

(28) Becke, A. D. Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 36, 3098−3100. (29) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (30) Becke, A. D. A New Mixing of Hartree-Fock and Local DensityFunctional Theories. J. Chem. Phys. 1993, 98, 1372−1377. (31) Becke, A. D. Density-Functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5852. (32) Fukui, K. The Path of Chemical Reactions − The IRC Approach. Acc. Chem. Res. 1981, 14, 363−375. (33) Gonzalez, C.; Schlegel, H. B. An Improved Algorithm for Reaction Path Following. J. Chem. Phys. 1989, 90, 2154−2161. (34) Collins, M. A. Molecular Potential Energy Surfaces for Chemical Reaction Dynamics. Theor. Chem. Acc. 2002, 108, 313−324. (35) Hratchian, H. P.; Schlegel, H. B. Accurate Reaction Paths Using a Hessian Based Predictor-Corrector Integrator. J. Chem. Phys. 2004, 120, 9918−9924. (36) Hratchian, H. P.; Schlegel, H. B. Using Hessian Updating to Increase the Efficiency of a Hessian Based Predictor-Corrector Reaction Path Following Method. J. Chem. Theory Comput. 2005, 1, 61−69. (37) Zhao, Y.; Truhlar, D. G. Density Functional for Spectroscopy: No Long-Range Self-Interaction Error, Good Performance for Rydberg and Charge-Transfer States, and Better Performance on Average than B3LYP for Ground States. J. Phys. Chem. A 2006, 110, 13126−13130. (38) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06 Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−241; Theor. Chem. Acc. 2008, 119, 535 erratum. (39) APT charges in 9: for C1: 0.163, for C3: 0.242. For APT, see: Cioslowski, J. A New Population Analysis Based on Atomic Polar Tensors. J. Am. Chem. Soc. 1989, 111, 8333−8336. (40) See Table S1 in the Supporting Information. (41) TS 1 (9.07 D) was lower in transition state energy (ΔG‡) than TS 2 (11.56 D) by 16.9 kJ mol−1; TS 12 (11.61 D) vs TS 14 (11.86 D): ΔG‡ 3.1 kJ mol−1. TS 13 (12.54 D) vs TS 16 (14.97 D): ΔG‡ 7.9 kJ mol−1. TS 15 (10.45 D) vs TS 17 (11.99 D): ΔG‡ 6.5 kJ mol−1. TS 24 (10.68 D) vs TS 25 (10.83 D): ΔG‡ 2.4 kJ mol−1. (42) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Intermolecular Interactions from a Natural Bond Orbital, Donor-Acceptor Viewpoint. Chem. Rev. 1988, 88, 899−926. (43) Wu, Y.-K.; West, F. G. Formal Homologous Aldol Reactions: Interrupting the Nazarov Cyclization via Carboalkoxylation of Alkynes. Org. Lett. 2014, 16, 2534−2357.

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