Mechanistic Study of the Direct Intramolecular Allylic Amination

Research Article pubs.acs.org/acscatalysis

Mechanistic Study of the Direct Intramolecular Allylic Amination Reaction Catalyzed by Palladium(II) Filipe J. S. Duarte,† Giovanni Poli,‡ and Maria José Calhorda*,† †

Centro de Quı ́mica e Bioquı ́mica, DQB, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, FR2769 Institut de Chimie Moléculaire, 4 place Jussieu, 75252 Paris Cedex 05, France

‡

S Supporting Information *

ABSTRACT: DFT calculations (PBE1PBE/6-31G(d,p), Def2-TZVPPD) were performed to study the intramolecular C−H amination of an unsaturated carbamate catalyzed by [Pd(LL)(OAc)2] (2), where LL is the bis(sulfoxide) ligand PhS(O)(CH2)2S(O)Ph. The coordination takes place by an associative path over a trigonal-bipyramidal transition state. The LL ligand undergoes a coordination shift from κ2S,S to κ1S, leaving an open position for binding of the substrate (C C). In the next step, the C−H activation, the transition state for the hydrogen abstraction from the substrate to form the σallyl complex has an energy of 124.0 kJ mol−1, which is the highest energy in the whole mechanism (TOF-determining transition state). The σ-allyl converts easily in the π-allyl, the acetic acid molecule leaving the coordination sphere. The remaining acetate receives the second hydrogen from the NH group, while the newly formed acetic acid molecule is replaced by the pendant arm of the LL ligand, and the cyclization takes place (nucleophilic attack). During these changes, the metal is reduced to Pd(0) in the form of the Pd(0) complex of the oxazolidinone product, the most stable species in the cycle (TOF-determining intermediate). Either the C−H activation or the Pd(0) oxidation may be the step determining the energy span of the reaction, depending on reaction conditions. KEYWORDS: direct allylic amination, palladium(II), reaction mechanism, catalysis, transition states, DFT calculations

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INTRODUCTION Metal-catalyzed C−H activation/functionalization is attracting increasing interest in organic synthesis,1−3 and computational studies4 are significantly enhancing the perception of such a transformation. Thus, for example, coupling of a C−H -containing substrate with a nucleophile (NuH) can now be conceived without the need for the classical prior oxidative functionalization of the atom desired to react as the electrophile, allowing the net replacement of the activated C−H atom by the nucleophile. The reactivity of C−H bonds is dependent on the environment of the carbon atom. While linear and trigonal carbon can be activated fairly easily, tetrahedral carbon atoms are (with a few exceptions) the least reactive ones, those in allylic positions being activated more easily than the remaining atoms. In particular, Rh,5 Ru,6 and Pd catalyses7,8 allow the direct allylic amination of an alkene.9−12 1,2- and 1,3-amino alcohols13 are key structural components in many pharmaceutical compounds14 and chiral ligands for asymmetric catalysis15 that can be conveniently obtained through ring opening of the corresponding 1,3-oxazolidin-2ones and 1,3-oxazinan-2-ones. These heterocycles can in turn result from a direct intramolecular Pd(II)-catalyzed allylic amination of N-sulfonyl carbamates derived from terminal © 2016 American Chemical Society

homoallyl and bis(homoallyl) alcohols (1), as described by White16 and Poli17 (Scheme 1). Both groups used the catalytic system Pd(OAc)2/PhS(O)(CH2)2S(O)Ph in the presence of a benzoquinone, as originally developed by White8a for the allylic internal acetoxylation of terminal alkenes. White and co-workers performed the cyclization reactions in THF16a (Table 1, entries 1−3) or DCE16b (Table 1, entries 4−6) and found that acceleration of the reactions and improvement of the yields16b could be obtained by either increasing the NH acidity by passing from tosyl to nosyl N-protecting group (Table 1, entries 4−6) or working in the presence of a Cr-salen complex (example not shown).10c Poli and co-workers showed that acceleration of the reaction and yield improvement could be obtained by running the reaction in acetic acid, which can affect the equilibria at different levels (Table 1, entries 7−11).17a These authors subsequently showed that a reversible intramolecular aminopalladation step can competitively take place. As a consequence, a direct intramolecular allylic amination can be observed only Received: September 18, 2015 Revised: January 28, 2016 Published: January 29, 2016 1772

DOI: 10.1021/acscatal.5b02091 ACS Catal. 2016, 6, 1772−1784

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ACS Catalysis

Scheme 1. 1,3-Oxazolidin-2-ones and 1,3-Oxazinan-2-ones through Direct Pd(II)-Catalyzed Intramolecular Allylic Amination

Table 1. Pd(II)-Catalyzed Intramolecular C−H Aminationa

entry

carbamate

n

R1

R2

R3

R4

yield (%)

dr anti:syn

ref

1 2 3 4 5 6 7 8 9 10 11

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k

0 0 0 1 1 1 0 1 1 1 1

i-Pr t-Bu n-Pr H Ph i-Pr H H Me i-Pr H

H H H H H Me H H H H H

H H H H H H H H H H Me

Ts Ts Ts Ns Ns Ns Ts Ts Ts Ts Ts

76 8 86 70 83 82 90 70 65 67 54

6:1 18:1 1.6:1

16a 16a 16a 16b 16b 16b 17a 17a 17a 17a 17a

1:6.8 1:2.5

1:4.9 1:8.1 1:2b

Reaction conditions: entries 1−3, Pd(OAc)2 (10 mol %), LL (15 mol %), PhBQ (1.05 equiv), THF, 45 °C, 72 h; entries 4−6, Pd(OAc)2 (10 mol %), LL (15 mol %), PhBQ (2.0 equiv), p-nitrobenzoic acid (10 mol %), oxygenated DCE, 45 °C, 24 h; entries 7−11, Pd(OAc)2 (10 mol %), LL (15 mol %), PhBQ (1.1 equiv), AcOH, 45 °C, 24 h. bIn this case the anti:syn assignment was unknown. a

alkene to benzoquinone Pd(0) exchange releases the final product and generates LLPd(η2-BQ) (IV), which is converted into dihydroquinone (DHQ) and [Pd(LL)(OAc)2] (step d). Poli focused on rationalizing17a the strong acceleration that occurs when the reaction is conducted in acetic acid in comparison to dichloromethane. DFT calculations showed that the acetic acid plays an important role in the metal reoxidation step. During this process, two protons are transferred stepwise from acetic acid to the coordinated p-benzoquinone (BQ), which is reduced to dihydrobenzoquinone (HBQ), while Pd(0) is oxidized to Pd(II) to regenerate [Pd(LL)(OAc)2] (Scheme 3), accompanied by coordination of the acetate anions. Fristrup and co-workers performed a combined experimental and computational study of the intermolecular allylic amination.18 Both kinetic isotope effect studies and the calculated mechanism pointed to the formation of one π-allyl palladium intermediate through a proton abstraction and suggested that this reaction step is “the rate-determining step (RDS)” of the reaction, though Pd(0) to Pd(II) oxidation required a comparable energy.17a,19 In this work, we propose to determine a full mechanism for the direct [Pd(LL)(OAc)2]-catalyzed intramolecular allylic amination of homoallyl- and bis(homoallyl)-substituted Ntosyl carbamates, using a DFT methodology.

when further evolution of the cyclic aminopalladated intermediate is forbidden or sufficiently slow.17b The general mechanism of this transformation, which has been partially investigated by computational means,17a,18 can be described according to the following four steps (Scheme 2). Alkene coordination to the Pd(II) gives complex I (step a) and is followed by abstraction of one allylic hydrogen (C−H activation) to afford the corresponding η3-allyl palladium complex II (step b). C−N bond ring closure follows with formation of the Pd(0)-ligated heterocycle III (step c). Then, Scheme 2. Proposed Catalytic Cycle for Intramolecular Amination17a

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RESULTS AND DISCUSSION Reaction Mechanism. We performed DFT calculations (see Computational Methods) to study in detail the steps of the direct [Pd(LL)(OAc)2]-catalyzed intramolecular amination of but-3-enyl-N-tosyl carbamate 1g, to afford the N-tosyl-4vinyloxazolidin-2-one 3g (Table 1, entry 7). 1773


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ACS Catalysis Scheme 3. Proposed Mechanism for the Pd Reoxidation

coordination. As a matter of fact, for the medium-sized basis set 6-31G**, which is commonly employed for this type (and size) of problem, the M06-2X functional leads to a marked preference for the κ2O,O coordination, which has not been experimentally observed, while both PBE and B3LYP perform correctly (see this and other results in Table S1 in the Supporting Information). However, the effect of choosing other kinds of functionals will be analyzed later. The first step of the reaction is the coordination of the carbamate 1g to the square-planar catalyst 2, which occurs through an associative substitution reaction involving the pentacoordinate transition state TS-1 (116.8 kJ mol−1; Scheme 4), where the CC bond of the substrate is still at a long distance from the metal (Pd−C bond lengths of 2.448 and 2.542 Å). The geometry is very close to a trigonal bipyramid, with an O−Pd−S axis (175°), the other O, S, and the midpoint of the CC bond defining a slightly distorted equatorial plane. In TS-1, one Pd−S bond is much longer than the other (2.408, 2.240 Å), while only a small asymmetry is detected for the two Pd−O bonds (2.141 and 1.990 Å). These features of the transition state set the stage for the coordination shift of the bidentate ligand from κ2S,S to κ1S, rather than the release of one acetate molecule. The hemilabile behavior of bidentate sulfoxide N-heterocyclic carbene ligands has been reported. The sulfoxide arm binds Pd(II) when a chloride is removed from its coordination sphere.23 The design of hemilabile ligands has played a significant role in synthetic chemistry and activity control of catalysts.24 The square-planar geometry is recovered and the two acetate ligands remain bound to the Pd(II) center in the new intermediate Int-1 (Pd−O 2.033 and 1.999 Å). The Pd−S bond is 2.290 Å, slightly longer than in complex 2, while the Pd−C distances of 2.162 and 2.212 Å to the alkene reflect the asymmetry of the molecule. It is interesting to note that in previous calculations this coordination step was not explored, having been assumed that in the relevant intermediate Pd(II) was bound to the κ2S,S ligand and only one κ2O,O acetate, in addition to the substrate.18 Such a cationic intermediate, 2AcO, results from a dissociative mechanism, and its energy is 111.9 kJ mol−1 higher than that of 2. The coordination of the substrate 1g takes place through another pentacoordinate transition state (TS-S1), where the double bond starts to bind and the acetate becomes monodentate (one Pd−O distance is already much longer than the other), and the energy is 189.2 kJ

The mechanism has been proposed to consist of four steps (Scheme 2): (1) alkene coordination, (2) C−H activation, (3) nucleophilic attack (intramolecular allylation), and (4) metal oxidation (catalyst regeneration). We modeled the cyclization reaction of the carbamate 1g catalyzed by Pd(OAc)2 in the presence of the ligand PhS(O)(CH2)2S(O)Ph (White catalyst) (Table 1, entry 7).20 The square-planar Pd(II) complex [Pd(LL)(OAc)2] (2), where LL represents the R,R isomer of the bidentate bis(sulfoxide) ligand PhS(O)(CH2)2S(O)Ph, is the starting species (the meso isomer of the ligand will be discussed later). A related complex, with two ethyl substituents on the C−C chain and chloride ligands (4) instead of acetate, has been structurally characterized by single-crystal X-ray diffraction.21,22 The choice of methodology to study the reaction was assisted by a good reproduction of the structural parameters of 4 (Figure 1). The bidentate ligand coordinates

Figure 1. Comparison between the experimental structure CEHTEO (4) and that calculated for [Pd(LL)(OAc)2] (2), with distances in Å.

the metal by the two sulfur atoms, so that the sulfoxide oxygen atoms are trans to each other. The calculations with the PBE functional lead to the same Pd−S (2.253 Å), SO (1.491 Å), S−C (1.828 Å), and C−C bond lengths (within less than 0.05 Å) as in the experimental structure (Pd−S 2.252, SO 1.482, S−C 1.845, 1.846 Å) and support the preference for the κ2S,S

Scheme 4. Schematic Mechanism for the Coordination of 1g to 2 and 3-D Representation of TS-1a

a

Relative Gibbs energies are given in kJ mol−1 and distances in Å. 1774


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Scheme 5. Proposed Schematic Mechanism for the C−H Activation and Intramolecular Allylation of the Carbamate Substrate 1g Catalyzed by Pd(OAc)2 in the Presence of PhS(O)(CH2)2S(O)Ph under Neutral Conditionsa

a

Relative Gibbs energies are given in kJ mol−1.

mol−1 (see Scheme S1 in the Supporting Information). This new mechanistic variant would be associated with an energetic span that is, at best, 72.4 kJ mol−1 higher than that passing through TS-1 and therefore was not pursued. The second step of the mechanism is the C−H activation. It occurs through an intramolecular abstraction of the hydrogen atom at the γ-carbon of the ligand chain (allylic hydrogen) of Int-1 by one of the two coordinated acetate ligands, according to a concerted metalation−deprotonation (CMD) type of mechanism25 (Scheme 5), for which the term ambiphilic metal ligand activation (AMLA) has also been proposed.26 The η1allyl intermediate Int-2 is formed first and then rearranges to the η3-allyl complex (Int-3-AcOH), where the acetic acid is very weakly bound to the acetate ligand. The double-bond configuration in Int-2 is E, and its rearrangement into Int-3AcOH generates a syn-substituted η3-allyl complex. The activation barrier for the former step is 69.0 kJ mol−1 and is associated with the C−H bond breaking in TS-2, leading to Int-2, while the η1−η3 allyl slippage occurs with a small barrier (23.6 kJ mol−1) to afford the more stable Int-3-AcOH (ΔG = −2.3 kJ mol−1). Loss of the acetic acid molecule generates Int3. In TS-2, as the uncoordinated CO oxygen of one acetate ligand approaches the allylic hydrogen atom (1.234 Å), one of the Pd−C bonds stretches to 2.462 Å, the other remaining at 2.094 Å, slightly longer than in Int-1, reflecting a η2−η1 haptotropic shift of the CC bond. The two Pd−O bond distances remain almost unchanged (2.073, 2.063 Å). Int-2 is a typical η1-allyl complex, with a Pd−C bond length of 2.037 Å, the spectator acetate (Pd−O 2.135 Å), and the newly formed

acetic acid molecule (trans to the allyl), with a 2.107 Å Pd−O bond to the carbonyl, while the hydroxyl oxygen is engaged in a O−H···O hydrogen bond with the pendant arm of the bis(sulfoxide) ligand (1.654 Å). The other arm remains bound to Pd (Pd−S 2.217 Å). The formation of the η3-allyl complex (Int-3) requires a rearrangement of the η1-allyl complex Int-2. This step generates two supplementary stereogenic units besides the two preexisting stereogenic centers of the R,R ligand: the allyl plane and the metal center. Two of the four epimeric structures that can be generated, (Int3up and Int-3Down, see SI) have been calculated and one is shown in Scheme 5). The epimer Int-3-AcOHDown (see SI) is found to be ∼3.6 kJ mol−1 more stable than Int-3-AcOHUp (Figure 2). Hence, only the former epimer was considered in the following discussion, though all energy values are shown in Scheme 5. The η1−η3 conversion of the allyl complex requires only a bending of the allyl chain, which approaches the γcarbon to Pd (2.371 Å in TS-3 and 2.126 Å in Int-3-AcOH). One interesting feature of TS-3 is the simultaneous approach of the uncoordinated sulfoxide oxygen (Pd−S 3.555 Å), while the acetic acid moves away from Pd and becomes involved in a hydrogen bond to the bound acetate instead (O−H···O 1.563 Å). In Int-3-AcOHDown, the three Pd−C bonds are 2.113, 2.126, and 2.121 Å, and there is only one Pd−O bond to the acetate and one Pd−S to the bis(sulfoxide). The acetic acid molecule is hanging from the acetate through an O−H···O hydrogen bond. The potentially bidentate bis(sulfoxide) ligand PhS(O)(CH2)2S(O)Ph has remained monodentate during this step. 1775


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Figure 4. Calculated transition state structures for the intramolecular cyclization (relative Gibbs energies in kJ mol−1).

(2.718 Å, in comparison with the existing Pd−S bond, 2.361 Å). The bis(sulfoxide) ligand regains its original κ2S,S bonding mode in the Int-4 complex, as shown by two Pd−S bonds at 2.337 and 2.338 Å. Thus, on passing from Int-3 to Int-4, the coordination site formerly occupied by the acetate ligand is replaced by the pendant sulfoxide. Although Int-4 has a higher energy than Int-3, a non-negligible amount of Int-4 should be formed in such an acid−base equilibrium.29 This second acetic acid molecule released interacts with the negatively charged nitrogen atom of the tosylate, in a charge-assisted O−H···N hydrogen bond, which helps to stabilize this intermediate (the same happens with the up and down conformers). The syn configuration of Int-3 is preserved in Int-4. Nucleophilic attack of the negatively charged nitrogen atom at the internal carbon atom of the η3-allyl moiety can take place through the two possible epimers Int-4Down/Up, yielding the five-membered intermediate Int-5, after passing through the corresponding transition states TS-5Down/Up (Figure 4 and Scheme 5), which show similar reaction barriers of 26.8 and 26.4 kJ mol−1 relative to Int-4Down/Up. The AcOH molecule

Figure 2. Two epimers of the calculated η3-allyl complex Int-3-AcOH, with selected distances in Å.

We can now plot the energy profile for the coordination and C−H activation steps (Figure 3). The complex Int-3-AcOH may lose acetic acid to afford Int-3 and continue the reaction. The third step in this transformation is cyclization (Scheme 5 and Figure 4), a step shared by the more common Pd(0)catalyzed allylations.27 The acetate ligand in the η3-allyl complex (Int-3) abstracts the proton from the N atom, to produce Int-4 plus a second acetic acid molecule, leaving a negatively charged nitrogen atom.28 In TS-4, the N−H distance at 1.495 Å is beyond a bond, the new OH bond is almost formed (1.066 Å), and a new Pd−S bond is being formed

Figure 3. Energy profile (relative Gibbs energies in kJ mol−1) for the coordination of the substrate 1g to complex 2 (first step) and the C−H activation (second step), to produce the η3-allyl complex Int-3. 1776


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Figure 5. Energy profile (relative Gibbs energies in kJ mol−1, only Down epimers are shown) for the intramolecular allylation (nucleophilic attack), to produce the oxazolidinone-Pd(0) complex (Int-5).

Figure 6. Energy profile (relative Gibbs energies in kJ mol−1) for the alkene 3g−benzoquinone Pd(0) exchange.

acetic acid molecule is replaced by the approaching pbenzoquinone, which forms two weak C−H···O hydrogen bonds to generate Int-5-BQ. Next, the substitution of the oxazolidinone ligand by p-benzoquinone occurs in a concerted way, through transition state TS-6 (Figure 6). The alkene to benzoquinone Pd(0) exchange is thermodynamically favored by 17.3 kJ mol−1, reflecting a stronger back-donation from Pd(0) to the π-acidic benzoquinone ligand than to the oxazolidinone 3g, as reported previously.17a The almost planar-trigonal coordination geometry of Pd(0) in Int-5 becomes distorted tetrahedral in TS-6. The Z−Pd−Q angle (Z, midpoint of the two sulfur atoms; Q, midpoint of the two carbon atoms of the vinyl substituents) drops from 177.5 to 151.4°, to allow the approach of the quinone, while the two Pd−S distances increase from ∼2.345 Å in Int-5-BQ to 2.362 and 2.388 Å in TS-6. The p-benzoquinone is only η1-bound (one Pd−C distance is 2.870 Å; the others are longer than 3.5 Å), while the Pd−C bonds to the oxazolidinone 3g are slightly longer in TS-6 than in Int-5-BQ (2.136 and 2.139 Å vs 2.097 and 2.117 Å). The activation energy (38.0 kJ mol−1) is small in comparison to other previous steps. After the transition state, the p-benzoquinone becomes η2 coordinated, with two short Pd−C bonds (2.115 Å). The Pd−S bonds shorten to the

reorients in order to form two hydrogen bonds. In the stronger one, O−H···O (1.755 Å), it acts as a donor to one oxygen atom of the Ts group, and in the weaker one, C−H···O (2.356 Å), the CO behaves as acceptor toward the proton bound to the carbon atom being attacked. These interactions are important to define the conformation of the five-membered ring in the transition state (TS-5), which will influence the selectivity. During this step, the Pd(II) catalyst is reduced to the Pd(0) complex Int-5, which carries a κ2S,S coordinated neutral bis(sulfoxide) ligand and a η2-alkene (the vinyl substituent of the newly formed oxazolidinone 3g). The energy profile for this step is shown in Figure 5 and starts from the η3-allyl complex Int-3, giving rise to the cyclic product and to a Pd(0) complex. The first step, from Int-3 to Int-4, has a barrier of 68.7 kJ mol−1, much higher than the hydrogen abstraction step to give Int-5. The last step of the catalytic cycle consists of the pbenzoquinone-triggered release of the oxazolidone from Int-5 (Figure 6) and catalyst regeneration (Figure 7). In Int-5, the oxazolidinone product 3g is coordinated to Pd(0) and interacts through a hydrogen bond with the acetic acid formed in TS-4. The oxidant molecule p-benzoquinone substitutes the alkene, in an associative process, as described in Figure 6. First, the 1777


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Figure 7. Energy profile (relative Gibbs energies in kJ mol−1) for the oxidation of Pd(0) to Pd(II).

Figure 8. Complete energy profile (relative Gibbs energies in kJ mol−1) for the formation of oxazolidinone 3g catalyzed by [Pd(LL)(OAc)2] (2), where LL = PhS(O)(CH2)2S(O)Ph.

the full mechanism, we also calculated it under the same conditions as for the previous steps (Figure 7). After release of the oxazolidinone 3g (Int-6), two acetic acid molecules approach p-benzoquinone, forming two strong O− H···O hydrogen bonds. In the first step, one acetic acid molecule transfers the proton to the quinone and starts to bind the metal as acetate, affording the high-energy species Int-7, through TS-7. In Int-7, Pd(0) has already been formally oxidized back to Pd(II), with an acetate and a κ 1C oxocyclohexadienyl as ligands. In the second transition state (TS-8), the latter ligand undergoes a κ1C to κ1O shift to afford the more stable Int-8 through the high-energy TS-8. Such Oto-C ligand rearrangement is thermodynamically favored, as the oxocyclohexadienyl ligand attains aromaticity to become the hydroquinone anion ligand, still stabilized by the hydrogen

normal 2.345 Å, and the metal recovers the trigonal environment (Z−Pd--Q angle 171.1°) in Int-6. The oxazolidinone 3g ends up weakly bound to the BQ (Figure 6) through C−H···O hydrogen bonds and can be easily released. On the other hand, the barrier for the reaction of Int5 with the substrate 1g, also present in the solution, is 22 kJ mol−1 higher than the barrier to form Int-6. Hence, this potential side path does not affect the course of the reaction (see Scheme S2 in the Supporting Information). Finally, in order to close the catalytic cycle, catalyst recovery requires oxidation of Pd(0) to Pd(II), carried out by BQ. This specific process has been studied by other authors in detail,17a,18 and it has been shown to occur stepwise, assisted by a double protonation (see also Scheme 3). In order to be able to analyze 1778


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ACS Catalysis Scheme 6. Schematic Mechanism for the Coordination of 1g to 2 under Acidic Conditionsa

a


Scheme 7. Proposed Mechanism for the C−H Activation of the Carbamate Substrate 1g Catalyzed by Pd(OAc)2 in the Presence of PhS(O)(CH2)2S(O)Ph under Acidic Conditionsa

a


Figure 8, TS-2 (C−H activation) seems to be slightly more important than reoxidation (TS-8). At the end of this exergonic reaction, the product 3g is formed and the catalyst is weakly bound to the HBQ. An energy of 26.2 kJ mol−1 is released to obtain the free complex 2, giving a Gibbs energy change for the global reaction 1g + BQ → 3g + HBQ = −68.1 kJ mol−1. Role of the Computational Methodology. Given the close energy barriers for two different events in the catalytic cycle, it seemed relevant to check the reliability of the method, namely, the role of dispersion corrections in the functional and the size of the basis sets. In order to address this, single-point energies of all the intermediates and transition states were recalculated with the empirical dispersion corrections added to the functional PBE1PBE, as well as with other functionals containing implicit dispersion correction (Table S2 and Figure S2 in the Supporting Information). No significant changes are detected in the overall energy profile, as the energy differences are small. The reaction energy span decreases from 137.8 to 118.1 with Grimme’s D3 dispersion correction and to 133.8 kJ mol−1 with the wB97XD functional (implicit correction), while the competing energy difference (ΔGTS‑8 − ΔGInt‑6‑AcOH) drops more quickly, from 135.4 to 99.3 and to 124.7 kJ mol−1, respectively. This indicates a sharper discrimination between the two possibilities, pointing to a reaction energy span defined by ΔGTS‑2 − ΔGInt‑6‑AcOH + ΔG2+HBQ. Further tests of the methodology were conducted, calculating single-point energies for the coordination and C−H activation steps (TS-1 and TS-2), as well as the reoxidation step (TS-7 and TS-8), and their reference intermediates (1g+2, Int-6AcOH, 2+HBQ) with other functionals and better basis sets. The free energies are collected in Table S3 in the Supporting

bond to acetic acid. Finally, the acetic acid transfers the second proton through the six-membered cyclic transition state TS-9, and the acetate coordinates to Pd(II), displacing the hydroquinone and regenerating the catalyst 2-HBQ. When a new substrate molecule approaches, a new cycle will start. The potential generation of the off-cycle intermediate 2-BQ (from 2 and BQ), which would inhibit the catalytic cycle, has also been considered. However, the energy of the corresponding transition state (see Figure S1 in the Supporting Information) has been calculated as 136.1 kJ mol−1, ∼20 kJ mol−1 higher than that of TS-1, the transition state relative to the coordination of the 1g substrate. Therefore, no such competition is at work. This scenario is in line with the notion that electrophilic d8 Pd(II) complex has more affinity for the electron-rich alkene substrate than for the better π-acceptor BQ. All the steps discussed above are assembled in Figure 8. The kinetic assessment of the AUTOF30 program identifies the TOF-determining intermediate (TDI) as Int-6-AcOH and the TOF-determining transition state (TDTS) as TS-2, corresponding to an energy span of 137.8 kJ mol−1 (ΔΔG = ΔGTS‑2 − ΔGInt‑6‑AcOH + ΔG2+HBQ), behaving as the apparent activation energy of the full cycle. TS-2 has the highest energy in the cycle and is associated with the proton abstraction step. On the other hand, a closer perusal of the energy profile indicates that the energy difference between the TDI (Int-6-AcOH) and TS-8 reaches 135.4 kJ mol−1 (ΔΔG = ΔGTS‑8 − ΔGInt‑6‑AcOH) which is very close to the reaction energy span of 137.8 kJ mol−1. Since this difference is not significant, it means that the reaction may be kinetically controlled at one or the other stage, depending on variable factors. Under the specific conditions of 1779


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ACS Catalysis Scheme 8. Formation of Int-11 and Its Dormant Charactera

a


ligand can easily move back and forth from the metal (Scheme 7). Despite the smaller energy barrier involved in the proton abstraction step when starting from Int-9, in comparison to that required when starting from Int-1, the global barrier from the defined energy reference of the reaction (1g+2) is lower on going through the first path (TS-2), as TS-11 (Scheme 7) is higher than TS-2 (Figure 8). Poli et al.17b provided evidence that treatment of N-tosyl carbamate 1g with 2 in AcOH brings about an initial rapid aminopalladation reaction, although the final isolated product (3g) results from an intramolecular direct allylation. This outcome has been interpreted in terms of the reversibility of the kinetically favored aminopalladation step, combined with a forbidden proxicyclic dehydropalladation of the six-membered aminopalladated intermediate (AmPI) Int-11. To find a confirmation on theoretical grounds for the experimentally observed behavior above, the calculation of a dehydropalladation path from 1g was studied, proceeding through Int-9, which was shown to be a high-energy species formed in acetic acid. Nucleophilic attack of the nitrogen atom in Int-9 at the alkene leads to the cyclic intermediate Int-11 with a barrier of 6.6 kJ mol−1, which is a relatively low barrier, in comparison to those discussed in Figure 8 for the intramolecular direct allylation. However, the transition state for the β-elimination step converting Int-11 in the products has an energy of 142.4 kJ mol−1 (TS-14), despite the unsaturation at the metal (Scheme 8). The high value of this energy in comparison to the energy of TS-2, involved in activating the allylic position (124.0 kJ mol−1), well accounts for the dormant character of the cyclic AmPI Int-11. A search for a dormant intermediate was also conducted from the more stable intermediate Int-1, but the energy for the transition state cyclization was 146.0 kJ mol−1, even higher than the energy of TS-14. This pathway is not accessible. The Substrate: Increasing the Chain Length (1h). As an extension of the above study, the intramolecular allylation reaction of pent-4-enyl-N-tosyl carbamate 1h,32 which provides an oxazinanone structure, was considered (Scheme 9). Thus, following the same strategy as adopted for substrate 1g, the energy profile of the transformation of 1h into Int-5h was calculated. The regeneration of the catalyst steps were not calculated, as they do not depend on the substrate. The energy profiles for the cyclizations of 1g and 1h are shown and compared in Figure 9. Rather predictably, the curves relative to the two reactions are very similar, with energy differences between the corresponding intermediates and transition states below 7 kJ mol−1, until Int-2, where the η1-allyl complex is formed. In fact, the chain length does not play a peculiar role until this point

Information and lead to small deviations from those discussed above. Reaction in Acetic Acid. The coordination of the substrate was also calculated in acetic acid, adding one proton to the system (2-H+, Scheme 6). Under these conditions, complex 2 is protonated to 2-H+, and the metal will remain coordinated to the bidentate ligand, an acetate anion, and a more weakly bound acetic acid molecule. Approach of substrate 1g leads to substitution of HOAc, a good leaving group, and coordination by the CC bond (Int-9-H+). Formal deprotonation of this species can occur by loss of one proton from the formed HOAc, the acetate anion remaining hydrogen-bonded to the NH group of the tosylate, leading to the new intermediate Int9, which can be directly compared, in terms of energy, to Int-1 formed under nonacidic conditions. Although the coordination of 1g takes place easily without an identifiable transition state (Scheme 6), the final intermediate Int-9 has a much higher energy (93.0 kJ mol−1) than Int-1 (55.0 kJ mol−1; see Scheme 5), even though Int-9 is stabilized by an intermolecular hydrogen bond, best described as N···H−O. In other words, AcOH as the solvent triggers ionization of the complex, displacing the acetate ligand to the outer-sphere region, to interact with the H−N group. This ionization is energetically very unfavorable. Therefore, this pathway is not competitive with the previously described one. The C−H activation step (Scheme 5 and Figure 3) could also proceed from Int-9, bearing the substrate coordinated through the CC bond (Scheme 7), one bound acetate, and an acetic acid molecule H-bonded to the formally deprotonated nitrogen atom (R2N−···HOAc). Such an N-deprotonation agrees with the slightly higher acidity of N-Ts carbamates in comparison to that of acetic acid.31 The hydrogen abstraction can be accomplished intramolecularly from the acetate ligand through TS-10 with a barrier of 57.7 kJ mol−1, affording the intermediate Int-10. The same intermediate can also be obtained through an intermolecular process starting from the H-bonded acetic acid, which abstracts the allylic proton, while donating its OH hydrogen to the R2N−. This step proceeds via TS-11 with a barrier of 37.6 kJ mol−1. Int-10 can be easily interconverted into Int-2 through TS-12 with a small barrier of 46.7 kJ mol−1 (Scheme 7), and the reaction proceeds in the same way as shown before in Figure 8 to the following step. Conversion between Int-10 and Int-2 interconnects the two aforementioned C−H activation paths (with and without AcOH). In this step, the sulfoxide ligand initially κ2S,S coordinated in both Int-9 and Int-10 undergoes a coordination shift back to κ1S in TS-12, opening a vacant site to allow coordination of acetic acid. The two Pd−O distances in TS-12 are 2.237 and 2.884 Å, which shows that one sulfoxide 1780


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The nature of the substrate does not significantly affect the high-energy transition steps. Other Effects. Alternatives can be envisaged for some of the steps. The first step involves the coordination of the substrate through the CC bond, which takes place by the associative mechanism described above. The bidentate ligand loses one arm (TS-1), its coordination mode becoming κ1S. The most obvious alternative, the loss of acetate with the bis(sulfoxide) ligand PhS(O)(CH2) 2S(O)Ph remaining bidentate, was addressed earlier and more in detail in Scheme S1 (SI). It involves higher energy intermediates and transition states. The square-planar complex 2 has been considered to exist with a bidentate bis(sulfoxide) ligand and two monodentate acetates, but is [Pd(κ1S)(OAc)(κ2OAc)] (2-mono) a likely alternative? Indeed, its energy is only 11.0 kJ mol−1 higher than that of 2. Its conversion to the transition state TS-1-mono corresponding to TS-1 requires only 91 kJ mol−1, in comparison to 116.8 kJ mol−1, and it looks as if this is a lower energy path (Scheme 10). However, both TS-1 and TS1-mono lead to the same intermediate Int-1, which reacts via the higher energy transition state TS-2 (Figure 8). Therefore, it is indeed not relevant whether the initial complex exists as 2 or 2-mono. In the beginning of this work, we chose the R,R enantiomer of the bidentate bis(sulfoxide) ligand PhS(O)(CH2)2S(O)Ph, which had already been used in other computational studies.17,18 Since we wondered whether the ligand configuration might influence the reaction outcome,16a we also calculated the full pathway starting from the meso isomer. The energy profile (Figure S3 and Table S4 in the Supporting Information) almost overlaps that shown in Figure 8. Despite some larger energy differences in intermediates and transition states that do not influence the reaction energy span, the relevant changes concern TS-2, which drops from 124.0 to 119.2 kJ mol−1, and Int-6-AcOH, which is destabilized from −81.9 to −75.5 kJ mol−1. The reaction energy span becomes

Scheme 9. Comparison of the Intramolecular Allylations of 1g and 1h

and even TS-3, associated with the η1-to-η3-allyl conversion, has essentially the same energy for both substrates. In contrast, the chain length plays a major role in differentiating the nucleophilic attack of the two cyclizations, owing to the different ring sizes of the heterocycles being formed. Indeed, the η1-allyl intermediate Int-2h is ∼11 kJ mol−1 more stable than the corresponding Int-2g, while this trend reverts at the η3allyl complex level, wherein Int-3g becomes more stable by 21.2 kJ mol−1. Remarkably, the two curves cross precisely at their TS-3 (same energy). The largest energy difference is observed at TS-4, associated with the intramolecular proton transfer step between the acetate ligand and the N-tosyl carbamate, requiring a large reorganization of the chain. This transition state appears to be more favored for the larger TS-4h than for TS-4g by 46.7 kJ mol−1. TS-4 are late (productlike) transition states, and the same trend is observed at the Int-4 level, though the energy difference attenuates to 28.0 kJ mol−1. The Pd(0) alkene complex (Int-5Down) is more stable for 1g (13.8 kJ mol−1).

Figure 9. Comparison of the two energy profiles (ΔG in kJ mol−1) for the direct allylic aminations of 1g (solid colored line) and 1h (dashed black line, values in parentheses) catalyzed by [Pd(LL)(OAc)2] (2), where LL = PhS(O)(CH2)2S(O)Ph. 1781


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ACS Catalysis Scheme 10. Comparison of Two Isomers of Complex 2 and the First Transition State

Figure 10. Catalytic cycle for the direct allylic amination of 1g catalyzed by [Pd(LL)(OAc)2] (2), where LL = PhS(O)(CH2)2S(O)Ph.

126.6 kJ mol−1, and the competing ΔGTS‑8 − ΔGInt‑6‑AcOH energy 137.8 kJ mol−1 becomes the new reaction energy span.

between κ1and κ2 makes it very flexible and is likely to be the key to rationalizing the chemistry of the particular system addressed in this work. The energy span of the reaction is not easy to define, competitive energies being calculated when considering ΔΔG = ΔGTS‑2 − ΔGInt‑6‑AcOH + ΔG2+HBQ or ΔΔG = ΔGTS‑8 − ΔGInt‑6‑AcOH. The first is higher (137.8 vs 135.4 kJ mol−1) when the reaction proceeds with the R,R isomer of the bis(sulfoxide) ligand but shifts when considering the meso form (126.6 vs 137.8 kJ mol−1). These values are influenced by the dispersion correction (smaller barriers), but the trend is the same. Probably other factors which cannot be quantified in this study may define whether C−H activation or Pd(0) oxidation is more determining. A final remark concerns competition between the catalyst form at a certain point of the cycle and competing ligands. Complex 2 reacts with the substrate 1g, but the oxidant BQ is also present; however, binding of 1g to the Pd(II) complex is kinetically preferred. On the other hand, the Pd(0) complex Int-5 is generated after cyclization and reacts readily with BQ, with a small barrier, to give a thermodynamically preferred BQ complex (Int-6), reflecting the higher π-acceptor capability of BQ in comparison to the alkene product and the substrate.

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CONCLUSIONS The computational study of the cyclization of a carbamate catalyzed by Pd(II) was performed, considering the four proposed steps of this intramolecular reaction. The overall reaction is favored by ∼68 kJ mol−1. The reaction mechanism is depicted in a catalytic cycle (Figure 10). The coordination of the substrate to 2 takes place in an associative way, through a trigonal-bipyramidal transition state (TS-1), with a high activation barrier, still overcome by the following C−H activation. Upon coordination, the CC of the substrate substitutes one arm of the bis(sulfoxide) ligand (LL) in the initial [Pd(LL)(OAc)2] (2). The two acetate ligands remain coordinated and will have a relevant role as a proton shuttles in the two following hydrogen transfer reactions (TS-2, to form the σ-allyl complex Int-2, and TS-4, to make possible the cyclization), giving rise to acetic acid molecules that leave the coordination sphere of the metal. After the loss of the second proton, the bis(sulfoxide) ligand recovers the κ2S,S coordination (Int-4) until the end of the reaction, stabilizing in particular the Pd(0) center. This capability of the ligand to shift 1782


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(5) (a) Conrad, R. M.; Du Bois, J. Org. Lett. 2007, 9, 5465−5468. (b) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006, 8, 1073−1076. (c) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835−4837. (d) Hannedouche, J.; Schulz, E. Chem. - Eur. J. 2013, 19, 4972−4985. (e) Lebel, H.; Trudel, C.; Spitz, C. Chem. Commun. 2012, 48, 7799− 7801. (f) Cochet, T.; Bellosta, V.; Roche, D.; Ortholand, J. Y.; Greiner, A.; Cossy, J. Chem. Commun. 2012, 48, 10745−10747. (6) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825−6828. (7) For book chapters and reviews on Pd-catalyzed allylic C−H activation, see: (a) Muzart, J. Bull. Soc. Chim. Fr. 1986, 65−77. (b) Åkermark, B., Zetterberg, K. Use of Alkenes as Precursors to πAllylpalladium Derivatives in Allylic Substitution with O, N, and Other Heteroatom Nucleophiles. Handbook of Palladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New York; 2002; Vol. 2, pp 1875−1885. (c) Grennberg, H., Bäckvall, J.-E. Allylic oxidations: palladium-catalyzed allylic oxidation of olefins. In Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, pp 243−255. (d) Moiseev, I. I.; Vargaftik, M. N. Coord. Chem. Rev. 2004, 248, 2381−2391. (e) Jensen, T.; Fristrup, P. Chem. - Eur. J. 2009, 15, 9632−9636. (f) Liu, G.; Wu, Y. Top. Curr. Chem. 2009, 292, 195−209. (g) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. - Eur. J. 2010, 16, 2654−2672. (h) Engelin, C. J.; Fristrup, P. Molecules 2011, 16, 951− 969. (i) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191−206. (j) Breder, A. Synlett 2014, 25, 899−904. (k) Liron, F.; Oble, J.; Lorion, M. M.; Poli, G. Eur. J. Org. Chem. 2014, 2014, 5863−5883. (l) Lorion, M. M.; Nahra, F.; Ly, V. L.; Mealli, C.; Messaoudi, A.; Liron, F.; Oble, J.; Poli, G. Chim. Oggi. 2014, 32, 30−34. (8) For examples of allylic C−H oxylations, see: (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346−1347. (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970−6971. (c) Vermeulen, N. A.; Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2010, 132, 11323−11328. (d) Covell, D. J.; White, M. C. Tetrahedron 2013, 69, 7771−7778. (e) Ammann, S. E.; Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2014, 136, 10834−10837. For an example of allylic C−H fluorination see: (f) Braun, M.-G.; Doyle, A. G. J. Am. Chem. Soc. 2013, 135, 12990−12993. (9) For book chapters and reviews on metal-catalyzed aminations see: (a) Hoosokawa, T. Aminopalladation and Related Reactions Involving Other Group 15 Atom Nucleophiles: AminopalladationDehydropalladation and Related Reactions. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2003. (b) Minatti, A.; Muñiz, K. Chem. Soc. Rev. 2007, 36, 1142−1152. (c) Wolfe, J. P.; Neukom, J. D.; Mai, D. H. Synthesis of Saturated Five-Membered Nitrogen Heterocycles via Pd-Catalyzed CN Bond-Forming Reactions. In Catalyzed Carbon-Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, Germany, 2010; Chapter 1, pp 1−34. (d) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981−3019. (e) Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013, 4, 4092−4106. (f) Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901−910. (10) For examples of allylic amination via allylic C−H activation, see: (a) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316−3318. (b) Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733− 4736. (c) Qi, X.; Rice, G. T.; Lall, M. S.; Plummer, M. S.; White, M. C. Tetrahedron 2010, 66, 4816−4826. (d) Yin, G.; Wu, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132, 11978−11987. (e) Mboyi, C. L.; Abdellah, I.; Duhayon, C.; Canac, Y.; Chauvin, R. ChemCatChem 2013, 5, 3014− 3021. (f) Strambeanu, I. I.; White, M. C. J. Am. Chem. Soc. 2013, 135, 12032−12037. (g) Osberger, T. J.; White, M. C. J. Am. Chem. Soc. 2014, 136, 11176−11181. (h) Nishikawa, Y.; Kimura, S.; Kato, Y.; Yamazaki, N.; Hara, O. Org. Lett. 2015, 17, 888−891. (I) Pattillo, C. C.; Strambeanu, I. I.; Calleja, P.; Vermeulen, N. A.; Mizuno, T.; White, M. C. J. Am. Chem. Soc. 2016, 138, 1265−1272. (11) Liu, J. Y.; Niu, H. Y.; Wu, S.; Qu, G. R.; Guo, H. M. Chem. Commun. 2012, 48, 9723−9725.

COMPUTATIONAL METHODS The geometries of all stationary points were fully optimized without symmetry constraints with the Gaussian 09 suite of programs33 employing density functional theory (DFT)34 with the functional PBE1PBE35 and the 6-31G(d,p)36 basis set for nonmetal atoms and Def2-TZVPPD37 for palladium. Solvent effects, obtained with the polarizable continuum model (PCM),38 with acetic acid as solvent were included in all optimizations. Harmonic vibrational frequencies were calculated for all stationary points to verify whether they are minima or transition states. IRC calculations complemented the identification of transition states. Zero-point energies and thermal corrections were taken from unscaled vibrational frequencies. Free energies of activation are given at 25 °C. The free energy values used in the work were obtained from single-point calculations, with the functionals PBE1PBE, wB97XD, 39 B97D3, 40 B2PLYPD3, 41 B3LYP, 42,43 and M062X,44 over the optimized geometries with the better basis set 6-311+G(2d,2p) for nonmetal atoms and all other conditions kept the same. All energies (in kJ mol−1) are calculated relative to the sum of the electronic energies of the isolated reagents obtained from the single-point calculations with the thermal corrections from the structure optimizations. The models were built on the basis of the CEHTEO structure obtained from the CSD.45 We checked that the geometry optimization of the starting Pd(II) complex was the same when obtained in the gas phase. Distances are always given in angstroms (Å) and energies in kJ mol−1. Three-dimensional structures were obtained with Chemcraft.46

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.5b02091. Computational data (PDF) Cartesian coordinates for the calculated structures (XYZ)

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AUTHOR INFORMATION

Corresponding Author

*E-mail for M.J.C.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.J.C. and F.J.S.D. are grateful to the Fundaçaõ para a Ciência e Tecnologia for financial support (SFRH/BPD/76878/2011 and UID/MULTI/00612/2013). G.P. thanks the CNRS, UPMC, for financial support. Support through CMST COST Action CM1205 (CARISMA) is also gratefully acknowledged.

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REFERENCES

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ACS Catalysis (12) For examples of aminopalladations, see: (a) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800−5807. (b) Tamaru, Y.; Kimura, M. Synlett 1997, 1997, 749−757. (c) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690−7691. (d) Joosten, A.; Persson, A. K.; Millet, R.; Johnson, M. T.; Bäckvall, J. E. Chem. - Eur. J. 2012, 18, 15151−15157. (13) Xie, Y.; Yu, K.; Gu, Z. J. Org. Chem. 2014, 79, 1289−1302 and refs 1 and 2 therein. (14) Mukhtar, T. A.; Wright, G. D. Chem. Rev. 2005, 105, 529−542. (15) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561−2576. (b) Evans, D. A.; Takacs, J. M.; Mcgee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109−1127. (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835−875. (16) (a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274−7276. (b) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707−11711. (17) (a) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.; Messaoudi, A.; Poli, G. Chem. - Eur. J. 2009, 15, 11078−11082. (b) Rajabi, J.; Lorion, M. M.; Ly, V. L.; Liron, F.; Oble, J.; Prestat, G.; Poli, G. Chem. - Eur. J. 2014, 20, 1539−1546. (18) Engelin, C.; Jensen, T.; Rodriguez-Rodriguez, S.; Fristrup, P. ACS Catal. 2013, 3, 294−302. (19) Grennberg, H.; Gogoll, A.; Bäckvall, J.-E. Organometallics 1993, 12, 1790−1793. (20) We chose the R,R isomer arbitrarily for our study. It was also used in previous calculations.17a The isomer composition is not declared in the commercial samples of complex 2 and in most papers dealing with its preparation. No difference was found by the authors of ref 16a in diastereoselectivity or yield using the racemic/meso ligand mixture. However, preparation of the meso form of 2 is described in ref 8e. (21) Allen, F. H. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 380− 388. (22) Pettinari, C.; Pellei, M.; Cavicchio, G.; Crucianelli, M.; Panzeri, W.; Colapietro, M.; Cassetta, A. Organometallics 1999, 18, 555−563. (23) Yu, K.-H.; Wang, C.-C.; Chang, I.-H.; Liu, Y.-H.; Wang, Y.; Elsevier, C. J.; Liu, S.-T.; Chen, J.-T. Chem. - Asian J. 2014, 9, 3498− 3510. (24) Braunstein, P.; Naud, F. Angew. Chem., Int. Ed. 2001, 40, 680− 699. (25) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118−1126. (26) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; PobladorBahamonde, A. L. Dalton Trans. 2009, 5820−5831. (27) For a review on the basics of this reaction, see: (a) Poli, G.; Prestat, G.; Liron, F.; Kammerer-Pentier, C.; Kazmaier, U. Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic Synthesis. Top. Organomet. Chem. 2011, 38, 1−63. For a review on computational approaches see: Kleimark, J.; Norrby, P.-O; Kazmaier, U. Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic Synthesis. Top. Organomet. Chem. 2011, 38, 65−93 For an example of intramolecular allylation of an N-tosyl carbamate see:. (b) Trost, B. M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339−1341. (28) According to the mechanism postulated by White (see for example ref 8b), once the (η3-allyl)palladium complex is formed, exchange between the bis(sulfoxide) ligand and the π-acidic benzoquinone takes place on the metal, which activates the (η3-allyl) palladium complex toward nucleophilic attack. (29) For an example of pronucleophile deprotonation by the acetate ligand of a (η3-allyl)palladium complex, see: Giambastiani, G.; Poli, G. J. Org. Chem. 1998, 63, 9608−9609. (30) (a) Kozuch, S. Wires Comput. Mol. Sci. 2012, 2, 795−815. See also: (b) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101−110. (c) Uhe, A.; Kozuch, S.; Shaik, S. J. Comput. Chem. 2011, 32, 978−985. (d) Kozuch, S.; Martin, J. M. L. ChemPhysChem 2011, 12, 1413−1418. (31) (a) Taylor, L. D.; MacDonald, R. J.; Rubin, L. E. J. Polym. Sci., Part A-1: Polym. Chem. 1971, 9, 3059−3061. (b) Taylor, L. D.; Pluhar, M.; Rubin, L. E. J. Polym. Sci., Part B: Polym. Lett. 1967, 5, 77. (32) We calculated only the first three steps of the pathway, as catalyst regeneration is identical with that of substrate 1g.

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Mechanistic Study of the Direct Intramolecular Allylic Amination

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