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A DFT mechanistic study on gold(I)-catalyzed cascade reaction of aminaloalkyne involving Petasis-Ferrier cyclization
Journal of Organometallic Chemistry xxx (2018) 1e7
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A DFT mechanistic study on gold(I)-catalyzed cascade reaction of aminaloalkyne involving Petasis-Ferrier cyclization Jing Shi, Siwei Bi*, Yuan-Ye Jiang, Yuxia Liu, Baoping Ling, Xiang-Ai Yuan School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 October 2017 Received in revised form 4 March 2018 Accepted 5 March 2018 Available online xxx
The reaction mechanism of gold(I)-catalyzed cascade reaction of aminaloalkynes involving PetasisFerrier arrangement was studied with the aid of density functional theory calculations. Our study showed that two mechanisms proposed by the Patil group and by us are possible. With the substrate bearing a -C≡C-H component the mechanism by us is preferred in which the reaction undergoes first a Petasis-Ferrier rearrangement. With the substrate bearing a -C≡C-Ar component the mechanism by the Patil group is preferred in which the reaction undergoes first a protodeauration step. In summary, both reaction mechanisms are related and reaction substrate governs which pathway is followed. © 2018 Published by Elsevier B.V.
Keywords: Gold(I) catalysis Hydroaminaloxylation Petasis-Ferrier rearrangement DFT
1. Introduction As a result of intrinsic p-activation property of gold catalysts [1,2], gold-catalyzed annulations of alkynes with weak nucleophiles are powerful tools to access highly functionalized carbo- and heterocycles [3e6]. Recently, gold-catalyzed cascade reactions involving Petasis-Ferrier cyclization were developed for synthesis of azaheterocycles. With terminal alkynes containing the N-C-O moiety as substrates, the Rhee, Zhang and Fustero groups reported Au(I)-catalyzed synthesis of piperidines [7e9]. Also with terminal alkynes as substrates, the Zhang group reported Au(I)-catalyzed synthesis of quinolizidines [10], where the appended aromatic ring in the substrate was found to be necessary. More recently, Patil and co-workers developed an efficient method to generate indolizidines and quinolizidines from readily available aminaloalkynes via Au(I)-catalysis [11]. The prototype reaction is shown in Scheme 1. With IPrAuOTf as the catalyst, the aminaloalkyne S converts to the indolizidine P in dichloroethane at 80 C. Indolizidines and quinolizidines are found to be important structural motifs in numerous natural products and pharmaceutically important compounds [12,13]. It is noteworthy that they found both terminal and internal alkynes operate efficiently for synthesizing indolizidines and quinolizidines.
* Corresponding author. E-mail address: [email protected] (S. Bi).
A plausible mechanism for the reaction shown in Scheme 1 has been proposed experimentally by Patil and co-workers (vide infra). In the current study, we proposed another related mechanism for the reaction with the substrate being a terminal alkyne, with the help of density functional calculations. We hope this study could gain deeper insights into the reaction and provide valuable information for designing relevant reactions. 2. Computational details All DFT calculations were performed using the Gaussian 09 package [14]. Molecular geometries of all complexes studied were optimized at the M06 level of density functional theory. The effective core potentials of Hay and Wadt with a double-z valence basis set (LanL2DZ) [15,16] were chosen to describe the Au atoms. In addition, the polarization functions were added for Au (zf ¼ 1.05). The 6-311G(d,p) [17,18] basis set was used to describe the C, H, O and N atoms. With the same level of theory and basis sets, frequency calculations in gas phase were performed to confirm all the stationary points as local minima (zero imaginary frequencies) or transition states (one imaginary frequency) and provide the thermal corrections to the single point energies in solution. Intrinsic reaction coordinate (IRC) calculations were conducted in order to verify each transition state actually connecting the two corresponding minima. To consider the solvent effect, we employed a continuum medium to do single-point calculations in the solution phase with the
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Scheme 1. Title reaction studied in the current study.
SMD [19,20] solvent model. Dichloroethane (DCE) is employed as the solvent in the calculations, corresponding to the experimental conditions. Single-point energies were obtained in solution using the M06 [21] functional with the SDD [22,23] pseudopotential for Au with the 6-311Gþþ(d,p) basis set for C, H, O and N. This computational method (M06 for optimization in gas phase)/(M06 [24e29] for single point energy in solution) has extensively proved feasible in the Au-catalyzed organic reactions. The Gibbs free energies in solution were obtained by adding the thermodynamic corrections calculated in gas phase to the single-point electronic energies in solution. In all the energy profiles, the calculated relative Gibbs free energies (kcal mol1) are presented and the relative enthalpies (kcal mol1, in parentheses) are also given for reference. 3. Results and discussion As shown in Scheme 2, Patil and co-workers present a plausible reaction mechanism of the reaction (Scheme 1). In catalytic cycle A, coordination of the aminaloalkyne S to the catalyst IPrAuþ followed by cyclization via nucleophilic addition of the hydroxyl oxygen to the internal acetylenic carbon affords the intermediate II. Then, a proton transfer from oxygen to the Au-bound carbon occurs, replacing the catalyst and generating oxazinane III. In catalytic cycle B, the p-intermediate IV undergoes a Petasis-Ferrier rearrangement via intermediate V to yield the product P and regenerate the catalyst IPrAuþ, completing the catalytic cycle. 3.1. Mechanism proposed in Scheme 2 With the help of density functional theory calculations, we first examine the plausible mechanism proposed by Patil and coworkers, and then examine the other related mechanism we proposed. Fig. 1 presents the Gibbs free energy profile for the mechanism by Patil and coworkers (Scheme 2). Considering proton
Scheme 2. A plausible reaction mechanism of the reaction shown in Scheme 1 proposed by the Patil group [11].
transfer is involved in the reaction and the direct transfer is difficult to achieve, we proposed substrate S that containing an OHcontaining species acts as a shuttle to promote the proton transfer. As shown in Fig. 1, intermediate 1 is afforded via coordination of S to the carbon-carbon triple bond of the catalyst IPrAuþ, accompanying another molecule of S forming a H-bond with the coordinated S. With the induction of the catalyst IPrAuþ, a nucleophilic attack of the hydroxyl oxygen toward the internal acetylenic carbon takes place, leading to the O-C2(sp2) bond formation with a bond length of 1.51 Å in 2. Here 2 corresponds to intermediate II proposed in Scheme 2. It is noteworthy that the O-C1(sp3) bond is elongated to be 1.50 Å from 1.43 Å in 1, appreciably weakened due to the O-C2 interaction (Fig. 2). Correspondingly, the N-C1 bond is relatively strengthened with a bond length reduction to 1.41 Å from 1.44 Å in 1, having some p bonding character. Clearly, the relatively low barrier of 10.4 kcal/mol is contributed by the nitrogen atom that stabilizes C1 by p bonding when C1-O bond is being weakened. The next step is proposed to undergo a proton transfer from the hydroxyl oxygen to the olefinic C3 with S acting as a shuttle. The barrier for hydrogen transfer under the assistance of a S molecule is calculated to be 16.4 kcal/mol. The significant exergonicity for the step by 38.2 kcal/mol is resulted from the C3-H bond formation. In 3, the intermediate organic product is afforded, corresponding to intermediate III proposed in Scheme 2. Subsequently, the PetasisFerrier rearrangement takes place to form intermediate 4, where the oxygen atom replaces C3 to form a bond with C1. This transformation can be viewed as the C4-C2 bond rotation as shown in the transition structure of TS3-4, leading to the oxygen inward and the C3 atom outward. The calculated distance of C1-C3 and C1-O in TS3-4 are 2.25 Å and 3.20 Å, respectively. In 4, the C1-C3 bond is formed and the final product is generated. Calculations related to the protodeauration process in other systems have been reported [30]. In the last step, the final product is generated and intermediate 1 is regenerated by the catalyst IPrAuþ continually coordinating to S. As to the direct hydrogen transfer, which means no shuttle assistance is involved, the barrier is calculated to be 30.4 kcal/mol as shown in the upper right of Fig. 1, infeasible under the experimental conditions (80 C). 3.2. Mechanism proposed in the current study The Gibbs free energy profile calculated for an alternative mechanism proposed in the current study is presented in Fig. 3. The first step 1 to 2 is the same as that shown in Fig. 1. From intermediate 2, instead of the S-assisted proton transfer (2 / 3) proposed in Fig. 1, the C2-C4 s bond rotation is suggested, with the hydroxyl being far away from C1 and the olefinic C3 being closer to C1. In TS2-6, the C1-O distance increases from 1.50 Å in 2 to 2.58 Å. After passing this transition state, the cyclization intermediate 6 is generated by forming the C1-C3 s bond. This step is significantly exergonic by 48.4 kcal/mol. Our calculations show that the electronic energy of TS2-6 is slightly higher than 2 in gas phase, but after considering the thermodynamic corrections in solvent TS2-6 becomes lower in energy than 2. To validate TS2-6, we conduct an E ~ r(C1-O) scan and the scan results show that TS2-6 is still slightly higher than 2 in energy (see Scheme S1 in the Supporting Information). The transformation similar to step 2 / 6 with the barrier having negative value has been reported by the Alabugin group [31]. The subsequent reaction is suggested to be the C3 protonation with concurrent IPrAuþ dissociation. One mode (6 / 7) is associated with direct attack of the hydrated proton toward C3 with concurrent C3-Au bond breaking. The calculated barrier of this step is 53.3 kcal/mol, indicating kinetically unachievable. Another mode (6 / 8) is related to the S-assisted C3-Au breaking. As shown in the
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Fig. 1. Calculated Gibbs free energy profile for the reaction in Scheme 1 based on the proposed mechanism by Patil and co-workers. The relative free energies and the enthalpies (in parentheses) are given in kcal/mol.
Fig. 2. Optimized geometries of key intermediates and transition states involved in the reaction mechanism shown in Fig. 1. The bond distances are given in Å. For clarity and simplicity, the hydrogen atoms attached to carbon atom, and the auxiliary ligand IPr coordinated to Au(I) are omitted.
transition structure of TS6-8 (Fig. 4), the hydroxyl oxygen atom of S nucleophilically attacks the gold center, giving rise to the C3-Au bond breaking and the Au)O(of S) dative bond forming. The enol-type of the final product is generated in 8. Compared to TS6-7, TS6-8 has lower energy that can be attributed to the forming Au)O(of S) dative bond. Form 8, one possibility is the S-assisted proton transfer to give an enol-ketotype conversion to afford the
final product, which has a barrier of 22.1 kcal/mol (8 / 9). The overall barrier from 6 to TS8-9 is as high as 34.1 kcal/mol, and thus this reaction pathway can be ruled out. Another possibility is that the weakly coordinated ROH can be easily replaced by the carboncarbon triple bond of the substrate S, giving the enol-type intermediate product 10 and regenerating the starting intermediate 1. The final step is the enol-ketotype conversion (10 / 11). With the
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Fig. 3. Calculated Gibbs free energy profile for the reaction mechanism proposed in the current study. The relative free energies and the enthalpies (in parentheses) are given in kcal/mol.
Fig. 4. Optimized geometries of key intermediates and transition states involved in the reaction mechanism shown in Fig. 3. The bond distances are given in Å. For clarity and simplicity, the hydrogen atoms attached to carbon atom, and the auxiliary ligand IPr are omitted.
help of a molecule of S, the barrier for the proton transfer via TS1011 is calculated to be 25.9 kcal/mol [32e34]. If the S assistance is not involved, the calculated barrier in Gibbs free energy is 55.7 kcal/mol (Fig. 3), indicating the S assistance is indispensable. Based on the energy profile shown in Fig. 3, we proposed that the last step, the enol-ketotype conversion (10 / 11), might be rate determining.
3.3. Comparison of the two mechanisms The two mechanisms shown in Figs. 1 and 3 diverge from 2. The Patil and co-workers proposed a protodeauration step as illustrated in Scheme 2 (II/III) and as calculated in Fig. 1 (2 / 3). Instead, we suggested a first Petasis-Ferrier rearrangement via C4-C2 bond
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rotation as shown in Fig. 3 (2 / 6). The energy profile comparison between the protodeauration step 2 / 3 and the first PetasisFerrier rearrangement step 2 / 6 is summarized in Fig. 5. Clearly, the first Petasis-Ferrier rearrangement is more favorable than the protodeauration process. Therefore, we suggested the reaction with the substrate being a terminal alkyne proceeds via the first PetasisFerrier rearrangement. For examining the reliability of the computational method, we employed M06L instead of M06 to re-calculate the transformations shown in Fig. 5, and found that the energy profile obtained is similar to the one in Fig. 5. The M06L-computed energy profile is given in Fig. S1 of the Supporting Information. In addition to the Petasis-Ferrier rearrangement with the presence of the substrate (step 2e6), the rearrangement with the presence of eOTf anion was also considered. The calculation results are presented in Fig. 6 and found the rearrangement is still barrierless. It is noteworthy that the experiment demonstrated that an intermediate compound corresponding to III shown in Scheme 2 was generated when the alkynyl hydrogen atom was replaced by an aryl group, which is contrary to the mechanism proposed in this work. For addressing this issue, we comparatively calculated the transformations of the C2-C4 bond rotation and the protodeauration as shown in Fig. 7. The calculation results indicated that the C2-C4 bond rotation transition state TS2-6-Ar is higher than the protodeauration transition state TS2-3-Ar by 1.4 kcal/mol in free energy and by 5.8 kcal/mol in enthalpy, supporting the mechanism proposed by the Patil group. The reason can be attributed to the steric effect caused by introduction of the bulky aryl group that hinders the C2-C4 bond rotation. As shown in the transition structure of TS2-6-Ar (the right side of Fig. 7), one hydrogen of the methylene linked to C1 has shortest distance of 2.61 Å with one carbon of the phenyl ring, which is obviously shorter than the C,,,H Van der Waala radius (2.9 Å) and hence hinders the C1-C3 bond forming. It can be deduced that if a substituent group is introduced into the phenyl group, the C2-C4 bond rotation would become more difficult due to the larger steric effect caused. As a result, we proposed that our proposed mechanism prefers a terminal alkyne while the
5
Fig. 6. Energy profile calculated for the Petasis-Ferrier rearrangement induced by OTf anion.
mechanism by the Patil group prefers a bulky group attached to the terminal alkynyl carbon. The brief catalytic cycle proposed by us was shown in Scheme 3. The starting intermediate I, formed by coordination of S to IPrAuþ, undergoes an Au-induced cyclization to afford intermediate II. Then, II undergoes a facile Petasis-Ferrier rearrangement via C-C s bond rotation to generate intermediate VI. With the binding of another molecule of S to the gold center, the S-coordinated catalyst VII is afforded and the enol-type VIII of the final product is released. The S-coordinated catalyst VII transforms to the starting intermediate I by the isomerization from HO-coordination to alkyne-coordination, completing the catalytic cycle. VIII undergoes an enol-ketotype conversion under the help of S, generating the
Fig. 5. Energy profile comparison between the protodeauration step 2 / 3 and the first Petasis-Ferrier rearrangement step 2 / 6.
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Fig. 7. Energy profile comparison between the protodeauration step 2-Ar/3-Ar and the first Petasis-Ferrier rearrangement step 2-Ar/6-Ar. As compared with the species shown in Fig. 5, a phenyl group instead of a hydrogen atom is introduced to the terminal alkynyl carbon.
rearrangement of II to afford intermediate VI. Then, the enol-type (VII) of the product P is generated, followed by the enol-keto conversion to yield the final product P. However, if the substrate with an aryl group instead of hydrogen atom attached to the alkynyl carbon, the mechanism proposed by the Patil group is preferred due to the large steric effect caused by the repulsion between the aryl group and the methylene linked to the nitrogen atom. Both pathways are possible and can be active, and which one will prevail will depend on the reaction substrate, or rather on the size of the group attached to the alkynyl carbon atom. Notes The authors declare no competing financial interests. Acknowledgment This work was supported by the National Natural Science Foundation of China (Nos. 21473100, 21702119, 21603116, 21403123, 21703118) and Shandong Provincial Natural Science Foundation, China (Nos. ZR2017QB001, ZR2017MB038). Scheme 3. Proposed reaction mechanism with the substrate being a terminal alkyne in the current study.
product P. It is noteworthy that when the substrate bearing a -C≡CAr component, the mechanism proposed by the Patil group is preferred. Which mechanism will prevail depends on the structure of a substrate. 4. Conclusions The mechanistic study on gold(I)-catalyzed hydroaminaloxylation and Petasis-Ferrier rearrangement cascade of aminaloalkynes was performed with the help of density functional theory calculations. Two possible reaction mechanisms were considered. The first mechanism is proposed by Patil and coworkers in which protodeauration of II is involved (Scheme 2 (II/III)). The other related mechanism is proposed in the current study where a Petasis-Ferrier rearrangement of II is suggested (Scheme 3 (II/VI)). Our calculations demonstrated that the substrate with a terminal alkyne undergoes a first Petasis-Ferrier
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Contents lists available at ScienceDirect
Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem
A DFT mechanistic study on gold(I)-catalyzed cascade reaction of aminaloalkyne involving Petasis-Ferrier cyclization Jing Shi, Siwei Bi*, Yuan-Ye Jiang, Yuxia Liu, Baoping Ling, Xiang-Ai Yuan School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, PR China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 October 2017 Received in revised form 4 March 2018 Accepted 5 March 2018 Available online xxx
The reaction mechanism of gold(I)-catalyzed cascade reaction of aminaloalkynes involving PetasisFerrier arrangement was studied with the aid of density functional theory calculations. Our study showed that two mechanisms proposed by the Patil group and by us are possible. With the substrate bearing a -C≡C-H component the mechanism by us is preferred in which the reaction undergoes first a Petasis-Ferrier rearrangement. With the substrate bearing a -C≡C-Ar component the mechanism by the Patil group is preferred in which the reaction undergoes first a protodeauration step. In summary, both reaction mechanisms are related and reaction substrate governs which pathway is followed. © 2018 Published by Elsevier B.V.
Keywords: Gold(I) catalysis Hydroaminaloxylation Petasis-Ferrier rearrangement DFT
1. Introduction As a result of intrinsic p-activation property of gold catalysts [1,2], gold-catalyzed annulations of alkynes with weak nucleophiles are powerful tools to access highly functionalized carbo- and heterocycles [3e6]. Recently, gold-catalyzed cascade reactions involving Petasis-Ferrier cyclization were developed for synthesis of azaheterocycles. With terminal alkynes containing the N-C-O moiety as substrates, the Rhee, Zhang and Fustero groups reported Au(I)-catalyzed synthesis of piperidines [7e9]. Also with terminal alkynes as substrates, the Zhang group reported Au(I)-catalyzed synthesis of quinolizidines [10], where the appended aromatic ring in the substrate was found to be necessary. More recently, Patil and co-workers developed an efficient method to generate indolizidines and quinolizidines from readily available aminaloalkynes via Au(I)-catalysis [11]. The prototype reaction is shown in Scheme 1. With IPrAuOTf as the catalyst, the aminaloalkyne S converts to the indolizidine P in dichloroethane at 80 C. Indolizidines and quinolizidines are found to be important structural motifs in numerous natural products and pharmaceutically important compounds [12,13]. It is noteworthy that they found both terminal and internal alkynes operate efficiently for synthesizing indolizidines and quinolizidines.
* Corresponding author. E-mail address: [email protected] (S. Bi).
A plausible mechanism for the reaction shown in Scheme 1 has been proposed experimentally by Patil and co-workers (vide infra). In the current study, we proposed another related mechanism for the reaction with the substrate being a terminal alkyne, with the help of density functional calculations. We hope this study could gain deeper insights into the reaction and provide valuable information for designing relevant reactions. 2. Computational details All DFT calculations were performed using the Gaussian 09 package [14]. Molecular geometries of all complexes studied were optimized at the M06 level of density functional theory. The effective core potentials of Hay and Wadt with a double-z valence basis set (LanL2DZ) [15,16] were chosen to describe the Au atoms. In addition, the polarization functions were added for Au (zf ¼ 1.05). The 6-311G(d,p) [17,18] basis set was used to describe the C, H, O and N atoms. With the same level of theory and basis sets, frequency calculations in gas phase were performed to confirm all the stationary points as local minima (zero imaginary frequencies) or transition states (one imaginary frequency) and provide the thermal corrections to the single point energies in solution. Intrinsic reaction coordinate (IRC) calculations were conducted in order to verify each transition state actually connecting the two corresponding minima. To consider the solvent effect, we employed a continuum medium to do single-point calculations in the solution phase with the
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J. Shi et al. / Journal of Organometallic Chemistry xxx (2018) 1e7
Scheme 1. Title reaction studied in the current study.
SMD [19,20] solvent model. Dichloroethane (DCE) is employed as the solvent in the calculations, corresponding to the experimental conditions. Single-point energies were obtained in solution using the M06 [21] functional with the SDD [22,23] pseudopotential for Au with the 6-311Gþþ(d,p) basis set for C, H, O and N. This computational method (M06 for optimization in gas phase)/(M06 [24e29] for single point energy in solution) has extensively proved feasible in the Au-catalyzed organic reactions. The Gibbs free energies in solution were obtained by adding the thermodynamic corrections calculated in gas phase to the single-point electronic energies in solution. In all the energy profiles, the calculated relative Gibbs free energies (kcal mol1) are presented and the relative enthalpies (kcal mol1, in parentheses) are also given for reference. 3. Results and discussion As shown in Scheme 2, Patil and co-workers present a plausible reaction mechanism of the reaction (Scheme 1). In catalytic cycle A, coordination of the aminaloalkyne S to the catalyst IPrAuþ followed by cyclization via nucleophilic addition of the hydroxyl oxygen to the internal acetylenic carbon affords the intermediate II. Then, a proton transfer from oxygen to the Au-bound carbon occurs, replacing the catalyst and generating oxazinane III. In catalytic cycle B, the p-intermediate IV undergoes a Petasis-Ferrier rearrangement via intermediate V to yield the product P and regenerate the catalyst IPrAuþ, completing the catalytic cycle. 3.1. Mechanism proposed in Scheme 2 With the help of density functional theory calculations, we first examine the plausible mechanism proposed by Patil and coworkers, and then examine the other related mechanism we proposed. Fig. 1 presents the Gibbs free energy profile for the mechanism by Patil and coworkers (Scheme 2). Considering proton
Scheme 2. A plausible reaction mechanism of the reaction shown in Scheme 1 proposed by the Patil group [11].
transfer is involved in the reaction and the direct transfer is difficult to achieve, we proposed substrate S that containing an OHcontaining species acts as a shuttle to promote the proton transfer. As shown in Fig. 1, intermediate 1 is afforded via coordination of S to the carbon-carbon triple bond of the catalyst IPrAuþ, accompanying another molecule of S forming a H-bond with the coordinated S. With the induction of the catalyst IPrAuþ, a nucleophilic attack of the hydroxyl oxygen toward the internal acetylenic carbon takes place, leading to the O-C2(sp2) bond formation with a bond length of 1.51 Å in 2. Here 2 corresponds to intermediate II proposed in Scheme 2. It is noteworthy that the O-C1(sp3) bond is elongated to be 1.50 Å from 1.43 Å in 1, appreciably weakened due to the O-C2 interaction (Fig. 2). Correspondingly, the N-C1 bond is relatively strengthened with a bond length reduction to 1.41 Å from 1.44 Å in 1, having some p bonding character. Clearly, the relatively low barrier of 10.4 kcal/mol is contributed by the nitrogen atom that stabilizes C1 by p bonding when C1-O bond is being weakened. The next step is proposed to undergo a proton transfer from the hydroxyl oxygen to the olefinic C3 with S acting as a shuttle. The barrier for hydrogen transfer under the assistance of a S molecule is calculated to be 16.4 kcal/mol. The significant exergonicity for the step by 38.2 kcal/mol is resulted from the C3-H bond formation. In 3, the intermediate organic product is afforded, corresponding to intermediate III proposed in Scheme 2. Subsequently, the PetasisFerrier rearrangement takes place to form intermediate 4, where the oxygen atom replaces C3 to form a bond with C1. This transformation can be viewed as the C4-C2 bond rotation as shown in the transition structure of TS3-4, leading to the oxygen inward and the C3 atom outward. The calculated distance of C1-C3 and C1-O in TS3-4 are 2.25 Å and 3.20 Å, respectively. In 4, the C1-C3 bond is formed and the final product is generated. Calculations related to the protodeauration process in other systems have been reported [30]. In the last step, the final product is generated and intermediate 1 is regenerated by the catalyst IPrAuþ continually coordinating to S. As to the direct hydrogen transfer, which means no shuttle assistance is involved, the barrier is calculated to be 30.4 kcal/mol as shown in the upper right of Fig. 1, infeasible under the experimental conditions (80 C). 3.2. Mechanism proposed in the current study The Gibbs free energy profile calculated for an alternative mechanism proposed in the current study is presented in Fig. 3. The first step 1 to 2 is the same as that shown in Fig. 1. From intermediate 2, instead of the S-assisted proton transfer (2 / 3) proposed in Fig. 1, the C2-C4 s bond rotation is suggested, with the hydroxyl being far away from C1 and the olefinic C3 being closer to C1. In TS2-6, the C1-O distance increases from 1.50 Å in 2 to 2.58 Å. After passing this transition state, the cyclization intermediate 6 is generated by forming the C1-C3 s bond. This step is significantly exergonic by 48.4 kcal/mol. Our calculations show that the electronic energy of TS2-6 is slightly higher than 2 in gas phase, but after considering the thermodynamic corrections in solvent TS2-6 becomes lower in energy than 2. To validate TS2-6, we conduct an E ~ r(C1-O) scan and the scan results show that TS2-6 is still slightly higher than 2 in energy (see Scheme S1 in the Supporting Information). The transformation similar to step 2 / 6 with the barrier having negative value has been reported by the Alabugin group [31]. The subsequent reaction is suggested to be the C3 protonation with concurrent IPrAuþ dissociation. One mode (6 / 7) is associated with direct attack of the hydrated proton toward C3 with concurrent C3-Au bond breaking. The calculated barrier of this step is 53.3 kcal/mol, indicating kinetically unachievable. Another mode (6 / 8) is related to the S-assisted C3-Au breaking. As shown in the
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Fig. 1. Calculated Gibbs free energy profile for the reaction in Scheme 1 based on the proposed mechanism by Patil and co-workers. The relative free energies and the enthalpies (in parentheses) are given in kcal/mol.
Fig. 2. Optimized geometries of key intermediates and transition states involved in the reaction mechanism shown in Fig. 1. The bond distances are given in Å. For clarity and simplicity, the hydrogen atoms attached to carbon atom, and the auxiliary ligand IPr coordinated to Au(I) are omitted.
transition structure of TS6-8 (Fig. 4), the hydroxyl oxygen atom of S nucleophilically attacks the gold center, giving rise to the C3-Au bond breaking and the Au)O(of S) dative bond forming. The enol-type of the final product is generated in 8. Compared to TS6-7, TS6-8 has lower energy that can be attributed to the forming Au)O(of S) dative bond. Form 8, one possibility is the S-assisted proton transfer to give an enol-ketotype conversion to afford the
final product, which has a barrier of 22.1 kcal/mol (8 / 9). The overall barrier from 6 to TS8-9 is as high as 34.1 kcal/mol, and thus this reaction pathway can be ruled out. Another possibility is that the weakly coordinated ROH can be easily replaced by the carboncarbon triple bond of the substrate S, giving the enol-type intermediate product 10 and regenerating the starting intermediate 1. The final step is the enol-ketotype conversion (10 / 11). With the
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Fig. 3. Calculated Gibbs free energy profile for the reaction mechanism proposed in the current study. The relative free energies and the enthalpies (in parentheses) are given in kcal/mol.
Fig. 4. Optimized geometries of key intermediates and transition states involved in the reaction mechanism shown in Fig. 3. The bond distances are given in Å. For clarity and simplicity, the hydrogen atoms attached to carbon atom, and the auxiliary ligand IPr are omitted.
help of a molecule of S, the barrier for the proton transfer via TS1011 is calculated to be 25.9 kcal/mol [32e34]. If the S assistance is not involved, the calculated barrier in Gibbs free energy is 55.7 kcal/mol (Fig. 3), indicating the S assistance is indispensable. Based on the energy profile shown in Fig. 3, we proposed that the last step, the enol-ketotype conversion (10 / 11), might be rate determining.
3.3. Comparison of the two mechanisms The two mechanisms shown in Figs. 1 and 3 diverge from 2. The Patil and co-workers proposed a protodeauration step as illustrated in Scheme 2 (II/III) and as calculated in Fig. 1 (2 / 3). Instead, we suggested a first Petasis-Ferrier rearrangement via C4-C2 bond
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rotation as shown in Fig. 3 (2 / 6). The energy profile comparison between the protodeauration step 2 / 3 and the first PetasisFerrier rearrangement step 2 / 6 is summarized in Fig. 5. Clearly, the first Petasis-Ferrier rearrangement is more favorable than the protodeauration process. Therefore, we suggested the reaction with the substrate being a terminal alkyne proceeds via the first PetasisFerrier rearrangement. For examining the reliability of the computational method, we employed M06L instead of M06 to re-calculate the transformations shown in Fig. 5, and found that the energy profile obtained is similar to the one in Fig. 5. The M06L-computed energy profile is given in Fig. S1 of the Supporting Information. In addition to the Petasis-Ferrier rearrangement with the presence of the substrate (step 2e6), the rearrangement with the presence of eOTf anion was also considered. The calculation results are presented in Fig. 6 and found the rearrangement is still barrierless. It is noteworthy that the experiment demonstrated that an intermediate compound corresponding to III shown in Scheme 2 was generated when the alkynyl hydrogen atom was replaced by an aryl group, which is contrary to the mechanism proposed in this work. For addressing this issue, we comparatively calculated the transformations of the C2-C4 bond rotation and the protodeauration as shown in Fig. 7. The calculation results indicated that the C2-C4 bond rotation transition state TS2-6-Ar is higher than the protodeauration transition state TS2-3-Ar by 1.4 kcal/mol in free energy and by 5.8 kcal/mol in enthalpy, supporting the mechanism proposed by the Patil group. The reason can be attributed to the steric effect caused by introduction of the bulky aryl group that hinders the C2-C4 bond rotation. As shown in the transition structure of TS2-6-Ar (the right side of Fig. 7), one hydrogen of the methylene linked to C1 has shortest distance of 2.61 Å with one carbon of the phenyl ring, which is obviously shorter than the C,,,H Van der Waala radius (2.9 Å) and hence hinders the C1-C3 bond forming. It can be deduced that if a substituent group is introduced into the phenyl group, the C2-C4 bond rotation would become more difficult due to the larger steric effect caused. As a result, we proposed that our proposed mechanism prefers a terminal alkyne while the
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Fig. 6. Energy profile calculated for the Petasis-Ferrier rearrangement induced by OTf anion.
mechanism by the Patil group prefers a bulky group attached to the terminal alkynyl carbon. The brief catalytic cycle proposed by us was shown in Scheme 3. The starting intermediate I, formed by coordination of S to IPrAuþ, undergoes an Au-induced cyclization to afford intermediate II. Then, II undergoes a facile Petasis-Ferrier rearrangement via C-C s bond rotation to generate intermediate VI. With the binding of another molecule of S to the gold center, the S-coordinated catalyst VII is afforded and the enol-type VIII of the final product is released. The S-coordinated catalyst VII transforms to the starting intermediate I by the isomerization from HO-coordination to alkyne-coordination, completing the catalytic cycle. VIII undergoes an enol-ketotype conversion under the help of S, generating the
Fig. 5. Energy profile comparison between the protodeauration step 2 / 3 and the first Petasis-Ferrier rearrangement step 2 / 6.
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Fig. 7. Energy profile comparison between the protodeauration step 2-Ar/3-Ar and the first Petasis-Ferrier rearrangement step 2-Ar/6-Ar. As compared with the species shown in Fig. 5, a phenyl group instead of a hydrogen atom is introduced to the terminal alkynyl carbon.
rearrangement of II to afford intermediate VI. Then, the enol-type (VII) of the product P is generated, followed by the enol-keto conversion to yield the final product P. However, if the substrate with an aryl group instead of hydrogen atom attached to the alkynyl carbon, the mechanism proposed by the Patil group is preferred due to the large steric effect caused by the repulsion between the aryl group and the methylene linked to the nitrogen atom. Both pathways are possible and can be active, and which one will prevail will depend on the reaction substrate, or rather on the size of the group attached to the alkynyl carbon atom. Notes The authors declare no competing financial interests. Acknowledgment This work was supported by the National Natural Science Foundation of China (Nos. 21473100, 21702119, 21603116, 21403123, 21703118) and Shandong Provincial Natural Science Foundation, China (Nos. ZR2017QB001, ZR2017MB038). Scheme 3. Proposed reaction mechanism with the substrate being a terminal alkyne in the current study.
product P. It is noteworthy that when the substrate bearing a -C≡CAr component, the mechanism proposed by the Patil group is preferred. Which mechanism will prevail depends on the structure of a substrate. 4. Conclusions The mechanistic study on gold(I)-catalyzed hydroaminaloxylation and Petasis-Ferrier rearrangement cascade of aminaloalkynes was performed with the help of density functional theory calculations. Two possible reaction mechanisms were considered. The first mechanism is proposed by Patil and coworkers in which protodeauration of II is involved (Scheme 2 (II/III)). The other related mechanism is proposed in the current study where a Petasis-Ferrier rearrangement of II is suggested (Scheme 3 (II/VI)). Our calculations demonstrated that the substrate with a terminal alkyne undergoes a first Petasis-Ferrier
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