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Mechanistic Study on Platinum-Catalyzed Domino Reaction of Benziodoxole and Pyrrole Homopropargylic Ethers for Indole Synthesis Xiaoping Man, Yuan-Ye Jiang, Yuxia Liu, and Siwei Bi* School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, People’s Republic of China S Supporting Information *

ABSTRACT: Benzene ring functionalization provides useful alternatives to access indole derivatives and has received much attention in recent years. In this work, the mechanism of Pt(II)-catalyzed cyclization/alkynylation of benziodoxole with pyrrole homopropargylic ethers to generate C5-alkenylated indole derivatives has been studied with the aid of density functional theory (DFT) calculations. We found that fivemembered-ring cyclization/six-membered-ring cyclization is competitive in the formation of an indole skeleton. The following aromatization stage prefers the reaction sequence bicarbonate-assisted deprotonation at the C3a position, H2CO3-promoted methoxy elimination at the C7 position, and bicarbonate-assisted deprotonation at the C6 position. In the last alkynylation stage, the oxidative substitution mechanism assisted by H2CO3 is found to be favored over the previously proposed 1,2-iodo shift and oxidative addition. The overall ratedetermining step is oxidative substitution. Additionally, an interesting substituent effect on chemoselectivity was investigated. The electronic and steric effects caused by methyl result in reverse chemoselectivity.

1. INTRODUCTION Indole derivatives are one of the most common types of heterocyclic compounds and are widespread in natural products.1 Also serving as important raw organic materials and fine chemical products, they have broad applications in the chemical industry and agriculture.2 Especially in the field of medicine, compounds containing an indole skeleton have received great attention due to their intrinsic bioactivity, which has gradually evolved into the mainstream in the development of new medicines.3 Various indole derivatives can be synthesized via two major strategies. One is related to installation or modification of the pyrrole ring of indole, and the other is related to direct or formal functionalization on the benzene ring of indole. The first strategy usually utilizes the fact that the pyrrole ring is electron rich and more reactive than the benzene ring toward an electrophile.4 As a result, electrophilic methods can afford pyrrole ring functionalized indole derivatives.5 In contrast, functionalizations on the less reactive benzene ring of indole have rarely been investigated. Yu6 reported olefination, arylation, and acetoxylation at the C6 position of indolines, while You7 reported the C6-alkylation of indole derivatives, but the substrates were limited to C2,C3disubstituted indoles. In more difficult challenges, Hartwig and co-workers reported the Ir-catalyzed selective C7-borylation of indoles,8 and Zhu et al. reported the rhodium-catalyzed direct C7-alkynylation of indolines in 2014.9 From a totally different route, Waser, Li, and co-workers recently successfully established a domino reaction of pyrrole © XXXX American Chemical Society

homopropargylic ether and ethynylbenziodoxole (EBX) to access formal C5-alkynylated indole derivatives (Scheme 1).2d Scheme 1. Title Reaction

The catalyst was optimized to be PtBr2, the additive base was NaHCO3, and the solvent was a 5/1 THF/CH3CN mixture. The products, benzene ring alkynylated indoles, have great potential value in medicinal, synthetic, and materials chemistry on the basis of further transformations of the tethered alkynes:10 for example, the 5-lipoxygenase as an inhibitor,11 the N-methyl-D-aspartate receptor as an antagonist,12 and the alkynylated carbazole as an organic sensor for the detection of TNT.13 The preliminary reaction mechanism for the domino cyclization/alkynylation accessing the C5-alkynylated product P has been proposed by Waser and Li. As shown in Scheme 2, coordination of PtX2 (X = Cl, Br) to R affords adduct A, which then undergoes cyclization to generate intermediate B. The ring Received: May 3, 2017

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DOI: 10.1021/acs.organomet.7b00338 Organometallics XXXX, XXX, XXX−XXX

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an oxidative addition/reductive elimination mechanism or direct nucleophilic attack of the organometallic intermediates onto the reagent EBX, which will be elucidated with theoretical methods. (4) An interesting substituent effect on chemoselectivity should be rationalized, because when the hydrogen at C7 is replaced by methyl, the C-6-alkynylated product is produced.

Scheme 2. Plausible Mechanisms Proposed by Waser and Li

2. COMPUTATIONAL METHODS All of our calculations were carried out with the Gaussian 09 program.15 The geometry optimizations were performed with the M06 functional in the gas phase.16 The basis set LANL2DZ17 was used for Pt, Br, Si, and I and 6-31G(d,p) for other atoms. Polarization functions were added for Pt (ζf = 0.993), Br (ζd = 0.428), Si (ζd = 0.428), and I (ζd = 0.289)18 in the calculations. Vibrational frequencies were computed at the same level of theory to confirm the stationary points as intermediates (zero imaginary frequency) or transition states (only one imaginary frequency) and also to obtain the thermodynamic corrections. Intrinsic reaction coordinate (IRC) calculations were performed to ensure that each transition state connects the corresponding minima.19 Solution-phase single-point energy calculations were conducted by performing single-point self-consistent reaction field (SCRF) calculations with the polarizable continuum model (PCM)20 with the M06 method and UAKS radii based on the gas-phase optimized structures. When necessary, the SMD model21 was also employed to give further examination of key steps. In Waser and Li’s experiments, a THF/CH3CN mixture (5/1 v/v) was used as the solvent, and the solvation effect was calculated using a single THF as solvent in our theoretical study. The SDD basis set22 for Pt, Br, Si, and I and 6-311++G(d,p) basis set for other atoms were used in the single-point energy calculations. Unless stated otherwise, all of the energies discussed in the main text are relative solution-phase Gibbs free energies (ΔG sol ), which were obtained by adding the thermodynamic corrections in the gas phase to the solution-phase single-point energies. Natural bond orbital (NBO) analyses23 were used to evaluate atomic charges.

expansion generates D from B via C. Then aromatization takes place by eliminating two protons and one methoxy (D → E). In the last stage, the C5-alkynylation of E with EBX occurs to deliver the desired product P and regenerate the catalyst PtX2. Associated with the development of indole chemistry, previous mechanistic studies were limited to the functionalization reactions of the pyrrole ring.14 As the first examples of the synthesis of alkynylated indoles and also rare examples that generate benzene ring functionalized indole derivatives, the reactions reported by Waser and Li deserve further study to clarify the detailed mechanism. In this work, some key issues related to the reaction were explored with the aid of density functional theory calculations. (1) Is the ring expansion from A to D direct or indirect via C? (2) What is the reaction sequence of the deprotonation and methoxy elimination in the transformation of D to E? (3) As Waser and Li pointed out, it is not clear whether the alkynylation step proceeds through

Figure 1. Energy profiles calculated for the PtBr2-induced cyclization (stage I). The free energies and enthalpies (in parentheses) are given in kcal/ mol. B


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Figure 2. Optimized geometries of key intermediates and transition states involved in the PtBr2-induced cyclization stage. The bond lengths and bond angles are given in Å and deg, respectively. All hydrogen atoms are omitted for clarity.

3. RESULTS AND DISCUSSION 3.1. Relative Stabilities of Various PtBr2 Adducts. In the reaction system, in addition to the presence of the catalyst PtBr2, there also exist the following species (Scheme 1): the substrates R and EBX, the base additive NaHCO3, and the solvent THF. All four species can coordinate with PtBr2. Thus, the relative stabilities of various PtBr2 adducts should be examined. To save computer time, the isopropyl is replaced with methyl in EBX, represented as EBX-Me. All of the possible PtBr2 adducts formed with the four species mentioned above were calculated (Figure S1 in the Supporting Information). The adduct (EBX-Me)Pt(HCO3)− (1 in Figure 1) is found to be most stable and is used as the starting material in our calculations. 3.2. PtBr2-Induced Cyclization (Stage I). Consistent with the proposal in Scheme 2, the PtBr2-induced cyclization was proposed to initiate the reaction in our calculations. Related Pt(II)-induced cyclizations have been reported experimentally and theoretically.24 The reaction mechanisms calculated for this stage are presented in Figure 1. Optimized key intermediates and transition states together with important structural parameters are shown in Figure 2. Complex 2 formed between (EBX-Me)PtBr2 and R was set as the zero energy reference. For simplification, the moiety (EBX-Me)PtBr2 (a 14e T-shaped species) is denoted as [Pt]. For the upcoming PtBr2-induced cyclization, a ligand exchange (1 → 2) is required, in which HCO3− is replaced by R. From 2, two cyclization modes are possible (paths 1 and 2). In path 1, under the induction of the π-acidic Pt(II) the terminal alkynyl C4 electrophilically attacks C7a via transition state TS2-3, generating a five-membered ring in intermediate 3.

The barrier calculated is 10.7 kcal/mol, and the reaction exergonicity is −11.2 kcal/mol. The PtBr2-induced cyclization makes intermediate 3 zwitterionic.25 From 3, two ring expansion paths were proposed. One is related to the C7− C3a bond formation accompanied by the C7a−C7 bond cleavage (the red line in Figure 1). Our calculations confirmed that the concerted C7−C3a bond formation and C7a−C7 bond cleavage complete the ring expansion with a barrier of 13.6 kcal/mol, delivering the more stable C6-metalated 6 that finally ends in the C6-alkynylated product P′. Another ring expansion path is related to the C4−C3a bond formation accompanied by C7a−C4 bond cleavage (the black line from 3 in Figure 1). Calculation results indicated that this ring expansion path undergoes a stepwise process rather than a concerted one. The C4−C3a bond formation takes place via transition state TS3-4 to afford intermediate 4, containing a three-membered carbocycle. As shown in Figure 2, the C7a−C4 bond in 4 is remarkably activated with a bond length increase from 1.54 Å in 3 to 1.63 Å in 4. The Pt−C bond is predicted to have some metal carbene character due to the bond decrease from 1.97 Å in 3 to 1.93 Å in 4. In the last step, the C7a−C4 bond cleavage via TS4-5 completes the ring expansion, delivering C5metalated 5 that finally ends in the C5-alkynylated product P. The extremely low activation barrier to the C7a−C4 bond breaking (0.2 kcal/mol) can be attributed to remarkable weakening of the C7a−C4 bond in 4 as discussed above. In comparison with the path that finally ends into P (the black line), the path finally ending in P′ (the red line in Figure 1) is clearly unfavorable because TS3-6 is significantly higher in energy than TS3-4 and TS4-5. The resonance structure 3′ indicates that the C4−C3a coupling should be facile. Therefore, C


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(Scheme 2). As is well-known, the halogen ions are less basic than bicarbonate that was added as an additive into the reaction system. We thus predict that it is the bicarbonate instead of bromide ion that helps eliminate the hydrogen atoms and the methoxy group. The energy profiles calculated for abstraction of the protons and methoxy are presented in Figure 3, and optimized geometries of key transition states involved in the aromatization stage are given in Figure 4. First, we examine the possibility of concertedly abstracting the methoxy and the adjacent hydrogen atom by forming MeOH. The activation barrier calculated for the formation of MeOH is extremely high (69.8 kcal/mol, 6 → TS6, the red line), indicating that this possibility can absolutely be excluded. Clearly, the overbending of the C7−C6−H and C6−C7−O bond angles makes TS6 very unstable and is thus responsible for the impossibility of the step. We also considered HCO3− serving as a shuttle to promote the concerted C6deprotonation/methoxy elimination, but we failed to locate the transition state. Instead, the transition state associated with the simple hydrogen elimination by HCO3− was always located (TS7, see below). Second, we examined the possibility of eliminating the hydrogen at C6 with the assistance of HCO3−. The activation barrier calculated for the hydrogen elimination step is 26.5 kcal/mol (7 → TS7, the pink line). This possibility can also be excluded, considering the reaction proceeds at room temperature. Third, we examined the possibility of first eliminating the hydrogen at C3a (the black line). The elimination of the hydrogen at C3a induced by HCO3− is calculated to surpass only a barrier of 8.1 kcal/mol (7 → TS7-8), with a great exergonicity leading to the elimination product 8. The driving force for the favorable kinetics and thermodynamics can be attributed to the expanded cyclic conjugation system in 8. Eliminating the methoxy (step 8 → 9) under the assistance of H2CO3 formed in the previous step is calculated to surpass a barrier of 15.1 kcal/mol. In addition, four other possible eliminations of the hydrogen at the C6 site and the methoxy at C7 site from 8 were also calculated but found to be less favorable kinetically (Figure S5 in the Supporting Information): (1) bicarbonate-assisted hydrogen elimination, (2) concurrent hydrogen and methoxy elimination by formation of methanol, (3) bicarbonate-assisted concurrent hydrogen and methoxy elimination by formation of methanol, and (4) carbonate-assisted concurrent hydrogen and methoxy elimination by formation of methanol. The calculation results demonstrated that the concerted elimination of both hydrogen and methoxy by formation of methanol is less favored over the stepwise eliminations. In 9, the conjugation system in the Pt(II) complex is further expanded along with generation of MeOH and regeneration of HCO3−. From 9, two pathways can be proposed. One is related to the 1,2-shift of the hydrogen at C6 to replace the [Pt] moiety to afford the Pt(II)-coordinated indole intermediate 11. The barrier calculated for the shift is 15.0 kcal/mol. The other is associated with the elimination of the hydrogen at C6 under the assistance of HCO3− (step 9 → 10). The barrier for the elimination is calculated to be 11.2 kcal/mol. Therefore, our calculation results confirmed that the elimination of the hydrogen at C6 occurs while the 1,2-shift of the hydrogen at C6 to afford a Pt(II)-coordinated indole intermediate does not. Up to the formation of intermediate 10, the aromatization is achieved. As outlined in Scheme 4, stage II proceeds via the following sequence: bicarbonate-assisted deprotonation at the C3a position, H2CO3-assisted methoxy elimination at the C7

generation of P′ proposed in Scheme 2 can be ruled out, consistent with the experimental observations. Let us move on to path 2 (the blue line in Figure 1), where C4 electrophilically attacks C3a to afford a six-membered ring, directly delivering intermediate 5. The free energy difference (ΔG⧧TS2‑5 − ΔG⧧TS2‑3) is calculated to be 0.6 kcal/mol. When the SMD model is employed, the difference is 0.1 kcal/mol (Figure S2 in the Supporting Information). It is noted that the EBX in the above calculations is modeled with isopropyl groups being replaced by methyl groups. With the original EBX to be taken into consideration, the difference is calculated to be 0.9 kcal/mol with the PCM model and 0.6 kcal/mol with the SMD model (Figures S3 and S4 in the Supporting Information). On the basis of the above calculation results, we predicted that both the five-membered and six-membered cyclizations are competitive, with the former being slightly favored. The similar stabilities of TS2-3 and TS2-5 arise from the balance between the electronic effect and the ring strain involved in the two transition states. The NBO charge calculations showed that the terminal alkynyl C4 (−0.251e) in 2 bears much more negative charge than the internal species (0.060e). As a result, in TS2-3 and TS2-5, C4 still bears a negative charge (−0.065e and −0.074e), C7a is positively charged (0.097e and 0.195e), and C3a is negatively charged (−0.256e and −0.332e). Therefore, C4−C7a coupling is favored over C4−C3a coupling, in favor of the stability of TS2-3. However, the ring strain involved in TS2-3 and the large structural distortion from 2 to TS2-3 do not favor the stability of TS2-3. As shown in Figure 2, the calculated C5−C6−C7 bond angle in TS2-3 is 106.8°, smaller than the general angle of about 109.3° at the sp3-hybridized carbon atom. However, in TS2-5, less structural distortion is involved, with the C5−C6−C7 bond angle being 110.7°. As summarized in Scheme 3, (i) the reaction with R is predicted to access C5-alkynylated product P rather than C6Scheme 3. Favorable Path for Pt(II)-Induced Cyclization

alkynylated product P′, agreeing with the experimental observations, and (ii) the paths via five-membered cyclization followed by ring expansion and via direct six-membered cyclization might both be operational, with the five-membered cyclization path slightly favored. 3.3. Aromatization by Abstracting Hydrogen and Methoxy (Stage II). After the PtBr2-induced cyclization of pyrrole homopropargylic ether (R) to afford the cyclization intermediate 5 in stage I, stage II follows to make it aromatic by eliminating the two hydrogen atoms at C6 and C3a and the methoxy group. In the preliminary mechanisms by Waser and Li, the hydrogen atoms seem to be eliminated by bromide ion D


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Figure 3. Energy profiles calculated for abstraction of the protons and methoxy. The free energies and the enthalpies (in parentheses) are given in kcal/mol.

Figure 4. Optimized geometries of key transition states involved in the aromatization stage. The bond lengths are given in Å. Some hydrogen atoms are omitted for clarity.

E


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position, and bicarbonate-assisted C6-deprotonation to generate C5-metalated indole. In comparison, direct methanol elimination (TS6), bicarbonate-assisted C6-deprotonation before methoxy elimination (TS7), concerted bicarbonateand H2CO3-assisted C6- deprotonation/methoxy elimination (Figure S5 in the Supporting Information), and 1,2-H shift were excluded. 3.4. Alkynylation of Indole (Stage III). Waser and Li et al. pointed out that the mechanism related to alkynylation of the Pt(II)-bonded indole was not clear. To explore how the alkynyl of EBX-Me is introduced onto C5 of the indole derivatives, we carried out a mechanistic study of the alkynylation process (Figures 5 and 6). Transformation from 10 to 13 is related to the formation of two hydrogen bonds between H2CO3 and the I-bonded oxygen (path I). In the presence of the hydrogen bonding, we failed to

Figure 6. Energy profiles calculated for C−C reductive elimination and generation of product P and regeneration of the catalyst 1. The free energies and the enthalpies (in parentheses) are given in kcal/mol. The bond distances are given in Å.

locate a general oxidative addition transition state leading to both Pt−alkynyl and Pt−I bond formation. Instead, we found the transition state TS13-14 that leads to only the Pt−alkynyl and the release of the O−I moiety, affording intermediate 14. There are two parts in 14. One is the 14e four-coordinated Pt(IV) complex with a seesaw structure, and the other is a

Figure 5. Energy profiles calculated for possible C−I bond cleavage pathways (paths I−III) and for carbonate-assisted C5 protonation (path IV). The free energies and the enthalpies (in parentheses) are given in kcal/mol. The bond distances are given in Å. F


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of EBX-Me, we reconsidered the four pathways and found that path I is still the most feasible with a close free energy barrier of 20.1 kcal/mol (Figure S9 in the Supporting Information). Subsequently in Figure 6, the complex with a seesaw structure is stabilized by HCO3−, giving the much more stable 18e complex 17, together with the release of the threecomponent species I. From 17, the C(sp)−C(sp2) reductive elimination takes place to generate the product-coordinated adduct 18, a 16e square-planar species with d8 configuration. This step needs to overcome a barrier of 14.4 kcal/mol (17 → TS17-18). Substitution with EBX-Me generates the product P and regenerates the starting material 1. Instead of HCO3−, the stabilization with EBX-Me as the ligand was also calculated and the reductive elimination step was found to be less favored in comparison to the case with HCO3− as the ligand (Figure S10 in the Supporting Information). 3.5. Substituent Effect on Chemoselectivity. Interestingly, one notable experimental phenomenon was observed, which is contrary to the case studied above. When C7 links a methyl instead of a hydrogen atom in the substrate (R-Me), the product P″ is generated with the alkynylation occurring at the C6 position in a yield of 54% (Scheme 5). This notable

three-component methanol−carbonate−(O−I moiety) (I), both of which get together by van der Waals interactions. The seesaw structure is understandable, because in a d6 configuration, both the empty dx2−y2 and dz2 orbitals overlap with the four ligand orbitals in the steric molecule. If a squareplanar structure were adopted, only the single dx2−y2 orbital would overlap with the four ligands, leading to the dz2 orbital being high in energy. Although the seesaw structure is coordinatively unsaturated, this step is still thermodynamically allowable. The strong hydrogen bonding involved in the threecomponent mixture methanol−carbonate−(O−I moiety) (I) is crucial for the stability of intermediate 14. In the structure of the three-component mixture, the phenoxyl O···H is found to be substantially longer than the carbonate O···H. Clearly, the two strongly electron withdrawing −CF3 groups are responsible for this scenario. The activation barrier to the C−I bond cleavage is calculated to be 21.1 kcal/mol. On the basis of the feature that the O−I moiety is released from the complex and the oxidation state of the platinum center increases from II to IV, we defined this transformation as an oxidative substitution process. In view of the fact that the complex in 14 is coordinatively unsaturated, we considered the possibility of providing additional ligands such as HCO3− and EBX-Me to stabilize the C−I bond breaking transition state TS13-14 (Figure S6 in the Supporting Information). However, our calculations showed that the transition states involving HCO3− and EBXMe transition states (−0.4 and −5.4 kcal/mol, respectively) are higher in free energy than TS13-14 (−14.2 kcal/mol). It is worth mentioning that TS13-14 is located on the condition of hydrogen bonding being involved. If the hydrogen bonding is absent in this process, such an oxidative substitution is unavailable. We performed a scan of r(C···I) vs the electronic energy (E), which demonstrated that E increases continuously as the C···I distance is elongated (Figure S7 in the Supporting Information). Additionally, we also found that the two electronwithdrawing −CF3 groups are helpful in decreasing the activation barrier because the −CF3 groups pull the C−I σ electron pair to the phenoxyl oxygen, making the oxygen atom more acidic. For comparison, the situation with −CF3 replaced by −CH3 was calculated, with a higher barrier of 25.4 kcal/mol (Figure S8 in the Supporting Information). Two other pathways were also considered, but they were found to be less favored both kinetically and thermodynamically. Path II is the general oxidative addition of the C−I bond to the Pt center. As shown in the step 10 → 15 (the red line in Figure 5), in the absence of the hydrogen bonding mentioned above, both the alkynyl and the O−I moiety can oxidatively add to Pt to give the 16e square-pyramidal structure 15. Path III (the pink line) is a 1,2-shift of the O−I moiety, giving a squareplanar vinylidene Pt complex25 (10 → 16). A related 1,2-shift of the O−I moiety has been reported previously.26 Path IV (the blue line) is the replacement of the [Pt] moiety by a proton under the assistance of carbonate to afford the Pt(II)coordinated indole intermediate 12 that is similar to 11 except that Pt(II) has different coordination modes with the benzene ring. Comparing paths I−IV, we can see that paths II−IV are less favorable energetically. On the basis of the four pathways, oxidative substitution (path I), general oxidative addition (path II), 1,2-shift of the O−I moiety (path III), and 1,2-shift of the hydrogen (path IV), we predicted that the C−I cleavage step prefers an oxidative substitution process (path I) with a free energy barrier of 21.1 kcal/mol. In addition, using EBX instead

Scheme 5. Reaction with a Methyl at C7

substituent effect on chemoselectivity inspired us to explore the origins. The Gibbs free energy change related to the reaction selectivity is shown in Figure 7. The five-membered cyclization via TS19-20 is favored over the six-membered cyclization via TS19-22 by 0.9 kcal/mol. When the original EBX is employed, the barrier gap is increased to 1.4 kcal/mol (Figure S11 in the Supporting Information). Thus, the path in blue ending in the C5-alkynylated byproduct cannot be considered. The ring expansion from 20 to 24 is easier than that one from 20 to 22 by 0.6 kcal/mol (TS23-24 vs TS21-22), roughly consistent with the product yield of 54%. When the original EBX is used, the energy gap is increased to 0.8 kcal/mol (Figure S12 in the Supporting Information). In comparison to the one-step ring expansion leading to the Pt-6-positioned intermediate (3 → 6, Figure 1), the corresponding transformation involves a two-step process (20 → 24, Figure 7). The barrier is lowered in the two-step transformation in comparison to 3 → 6. The important factor is that the methyl can effectively stabilize the C7 cation on breaking the C7−C7a bond. Thus, the barrier 20 → TS20-23 associated with C7−C7a bond breaking is lowered by 6.1 kcal/ mol in comparison to 3 → TS3-6. The following step is C7 electrophilic attack toward C3a with a small barrier of 6.4 kcal/ mol, delivering the Pt-6-positioned cyclization intermediate 24. We conclude that the presence of methyl that stabilizes the C7 cation is the major factor leading to the overall barrier of the ring expansion being lowered. In a comparison of the two pathways, 3 → 5 in Figure 1 and 20 → 22 in Figure 7, the latter has clearly a higher overall barrier than the former. The steric repulsion between the methyl and the pyrrole involved in TS20-21 and TS21-22 is responsible for their instability. The G


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Figure 7. Energy profiles calculated for the PtBr2-induced cyclization in the reaction shown in Scheme 5. The free energies and the enthalpies (in parentheses) are given in kcal/mol.

to the facile C4−C3a coupling, which rationalizes why only the product via the Pt-5-positioned cyclization can be obtained. (2) In the aromatization process (stage II), the elimination of hydrogen atoms and methoxy is completed under the assistance of bicarbonate and carbonate, which takes place in this order bicarbonate-assisted C3a deprotonation, H2CO3-promoted C7 elimination of the alkoxy group, and bicarbonate-assisted C6 deprotonation. (3) In the process of indole alkynylation (stage III), alkynylation preferentially undergoes an oxidative substitution with the help of carbonic acid, which facilitates the release of alcoholate by forming a hydrogen bond. The general oxidative addition to concertedly form both a Pt−alkynyl bond and Pt−I bond and the path via a 1,2-shift of the O−I moiety were predicted to be less favorable both kinetically and thermodynamically. Meanwhile, the oxidative substitution is predicted to be the overall rate-determining step for the whole catalytic cycle. (4) The substituent effect on chemoselectivity was investigated with hydrogen being replaced by methyl. The electronic effect resulting from methyl favors Pt-6-positioned cyclization, and the steric effect resulting from methyl disfavors Pt-5-positioned cyclization. We hope this theoretical study will give a deeper understanding for such kinds of reactions and inspire the development of synthesizing alkynylated indoles, especially for the methods based on domino cyclization processes.

closest H···H distances in the two transition states are calculated to be 2.24 and 2.21 Å, respectively, remarkably shorter than those in 20 and 21. In summary, two factors make the chemoselectivity reversed when hydrogen is replaced by methyl. One is the methyl electrophilicity that facilitates C−C bond breaking, favoring Pt6-positioned cyclization. The other is the steric effect involved by the methyl with the pyrrole ring, disfavoring the Pt-5positioned cyclization. In addition, the reaction with C3-subsituted pyrrole was considered. Only the first stage related to the regioselectivitydetermining process was calculated, and we found that similar steps are involved as in the reaction of the C2-subsituted pyrrole. Calculation results are given in Figure S13 in the Supporting Information. The following aromatization and alkynylation are predicted to undergo steps similar to those in the reaction of the C2-subsituted pyrrole, and so we did not perform further calculations.

4. CONCLUSIONS Pt-catalyzed domino reactions of benziodoxole and pyrrole homopropargylic ethers provide a novel and valuable alternative to synthesize benzene ring alkynylated indole derivatives. In this work, the related mechanism has been theoretically studied with the aid of DFT methods. The whole catalytic cycle was found to include three major stages: i.e., PtBr2-induced cyclization, aromatization, and benzene ring alkynylation. (1) In the PtBr2-induced cyclization (stage I), the cyclization is finished via two competitive pathways, direct six-membered ring cyclization and five-membered ring cyclization, with the latter pathway being slightly favorable. The Pt-5-positioned cyclization is preferred over the Pt-6-positioned cyclization due

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.7b00338. H


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Relative stabilities of different catalyst precursors, results based on SMD model or original structures, relaxed energy surface scan, unfavored pathways, structure− activity relationship in oxidative substitution, energy profile of the cyclization of C3-subsituted pyrrole (PDF) Cartesian coordinates and calculated energies (in hartrees) of all structures presented herein (XYZ)

AUTHOR INFORMATION

Corresponding Author

*E-mail for S.B.: [email protected]. ORCID

Yuan-Ye Jiang: 0000-0002-4763-9173 Yuxia Liu: 0000-0003-1139-8563 Siwei Bi: 0000-0003-3969-7012 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was jointly supported by the National Natural Science Foundation of China (Nos. 21473100 and 21403123), Project of Shandong Province Higher Educational Science and Technology Program (No. J14LC17), and Opening Foundation of Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers (No. KLDTTM2015-9).

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Article

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