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Home > Theoretical studies on Rh(III)-catalyzed regioselective C–H bond cyanation of indole and indoline
Theoretical studies on Rh(III)-catalyzed regioselective C–H bond cyanation of indole and indoline
Chao Deng, Yingxin Sun, Yi Renc and Weihua Zhang
1. Introduction
Indole compounds as one of the most important alkaloids can be found in many natural products and pharmaceuticals due to their significant biological activities. Furthermore, cyanoindole moieties as versatile building blocks were widely utilized in medicinal synthesis2 and materials chemistry3 owing to the ‘CN’ unit, such as pharmaceuticals, agrochem- icals, dyes, and natural products. Therefore, the development of efficient synthetic methodologies for indole cyanation is of great importance.4 During the past few decades, many preparation methods of cyanoindoles have been developed.4–12 However, the most efficient method for cyan- ation of indole is transition-metal catalyzed direct C–H functionalization with nonmetallic cyano-group sources because of their atom economy and they can avoid highly toxic metal cyanides compared with indole halides and indole boronic acids. The transition-metal complexes include Rh,5 Pd,6 Cu,7 Co,8 Zn,9 Ru,10 Fe11 and other Lewis acids.12 To the best of our knowledge, until now there have been no reports of theoretical studies on the detailed reaction mechanism of transition-metal catalyzed regioselective indole C–H cyanation.
In 2015, the Kim group reported a Rh(III)-catalyzed C2–H cyanation of indole directed by the pyrimidine group (eqn (1)) and C7–H cyanation of indoline directed by the carbonyl group (eqn (2)) with NCTS.5a It is well known that indoline compounds can be easily converted into indoles. The plausible reaction mechanism shown in Scheme 1 has been proposed by us based on previous work5a to account for the regioselective C–H cyanation of indole. The mechanism of C2–H cyanation starts with the C2–H bond activation of the indole substrate by [Cp*RhOAc]+ species to give a five-membered rhodacycle inter- mediate B. Then, the coordination of NCTS to the metal center generates an 18-electron intermediate C, which undergoes an insertion of the cyano group into the C–Rh bond to give the intermediate D. Next, the intermediate D goes through a β-N elimination to yield the product and intermediate E. Finally, the intermediate E is protonated to regenerate the active cata- lytic species A. For the C7–H cyanation, the mechanism is similar to the C2–H cyanation.
It is interesting to observe the regioselective C–H bond cya- nation of indole and indoline. However, many details of the reaction mechanism remain unclear. For example, how different indole and indoline substrates affect the regio- selectivity of C–H cyanation and the detailed reaction mecha- nism. Thus density functional theory calculations will be per- formed to study the reaction mechanism of the Rh(III)-catalyzed C–H cyanation of indole and indoline with NCTS. We hope our study can provide an understanding of the factors that control the regioselectivity of C–H cyanation, in order to realize diversi- fied and site-selective functionalization of indoles.
2. Computation details
All calculations in this study were performed with the Gaussian 09 programs.13 Geometry optimizations of all struc- tures were carried out at the M06 level of theory.14 The DFT method is reasonable and has been proved to be reliable in numerous theoretical studies of mechanisms of Rh-catalyzed reactions.15 Frequency analysis was carried out at the same level of theory to confirm the characteristics of the stationary points with no imaginary frequency for minima and only one imaginary frequency for the saddle points. Calculations of intrinsic reaction coordinates (IRC) were conducted to confirm that saddle points connect two relevant minima.16 The 6-31G
(d)basis set was used for N, C, H, O and S atoms, while the 6-31G (d, p) basis set was selected for hydrogen atoms on both C2 and C7 positions in all reaction pathways. The effective core potential (ECP) basis set (LanL2DZ)17 was employed for Rh atoms. Moreover, the polarization functions for Rh (ζf = 1.35) were added.18
To take the solvent effects into account, single-point ener- gies were computed with the same functional in conjunction with the SMD19 solvation model based on the gas-phase opti- mized geometries. In the M06-SMD calculations, a larger basis set 6-311++G(d, p) was used for all non-metal atoms and the basis set for Rh remains unchanged. Dichloroethane (DCE) was employed as the solvent. Natural bond orbital (NBO)20 analysis was performed by using the NBO program as implemented in the Gaussian 09 software package at the same level of theory. The solvation-corrected Gibbs free energies (at 298.15 K) were given in kcal mol−1 for the following discussion.
3. Results and discussion
3.1Equilibrium between different Rh(III)-complexes
The reactions shown in eqn (1) and (2) were carried out in the presence of [Cp*RhCl2]2, AgSbF6 and NaOAc. According to the previous theoretical studies,15b,21 the species of [Cp*RhOAc]+ was commonly chosen as the active catalyst in this catalytic system. Thus in this reaction system N-cyano-N-phenyl-para- methylbenzenesulfonamide (NCTS) directed indole or indoline can coordinate with [Cp*RhOAc]+ before the C–H activation process. As shown in Scheme 2, the complex of substrate NCTS coordinated 1c has the lowest free energy compared with two other intermediates (1a and 1b). Therefore, it is reasonable to assume the intermediate 1c as the reference point throughout the text. Moreover, the energy differences between the three intermediates are less than 7 kcal mol−1, which suggest that these intermediates are in rapid equilibrium with each other.
3.2. C–H cyanation of indole with NCTS
As mentioned in the Introduction, when the substrate is indole, C2–H bond cyanation was experimentally observed, and the reaction mechanism (Scheme 1, right-hand side) con- sists of four major steps: C–H activation, cyano group inser- tion, β-N elimination and regeneration of active species.
3.2.1 C2–H cyanation of indole. Fig. 1 shows the energy profile for this pathway. First, we discuss the C–H activation step. Starting from the three-legged piano stool structure 1c, via a ligand exchange from NCTS to pyrimidine directed indole to give an 18-electron intermediate 1a, then it iso- merizes to intermediate 2a, which is a precursor complex for the process of C2–H bond activation. Based on the previous studies of Rh(III)-catalyzed C–H activation in the presence of−OAc, the concerted metalation-deprotonation (CMD) process is
the most favorable pathway compared with σ-bond metathesis, oxidation addition and electrophilic substitution.15b–d,21 Thus in this study the proton at the C2 position can be deprotonated by a CMD process through the six-membered ring transition state TS2a to afford a five-membered rhodacycle intermediate 3a. As shown in Fig. 1a, the free energy barrier for the C–H acti- vation process is calculated to be 14.1 kcal mol−1. From 3a, dis- sociation of one molecule of acetic acid gives a 16-electron five- membered rhodacycle species 4a, and the overall C–H activation step is exergonic by 3.3 kcal mol−1. Then one molecule of the NCTS substrate comes in and coordinates to the metal center with the terminal nitrogen atom of the cyano group, giving intermediate 5a, and the activation barrier for this step is
5.7 kcal mol−1. Subsequently, intermediate 5a undergoes a high energy cyano group insertion step via the four-membered ring transition state TS5a to afford intermediate 6a, and the energy barrier for this step (5a → TS5a) is 25.6 kcal mol−1.
Next, let us discuss the β-N elimination step (Fig. 1b). From intermediate 6a, the coordination of one oxygen atom of the sulfonamide group to the Rh center instead of the nitrogen atom of the pyrimidine directing group yields 7a. From 7a, the β-N elimination process occurs via the transition state TS7a to afford the product P1 with a barrier of 24.9 kcal mol−1.
Finally, let us discuss the process of regeneration of the active catalytic species 1c. As shown in Fig. 1b, intermediate 8a reacts with an incoming HOAc via the eight-membered ring transition state TS9a to provide byproduct 4-methyl-N-phenyl- benzenesulfonamide and regenerate the active catalytic species 1c. The energy barrier for this step is only 13.2 kcal mol−1, which suggests that once the product is formed, the protonation of the sulfonamide rhodium complex is very facile.
Based on the more stable catalyst (Cp*Rh(OAc)2), the C–H activation is endergonic which is immediately followed by cyano group insertion. According to the literature report,15c,22 the rate determining step is the combined processes of C–H activation and the cyano group insertion, that is, the C–H acti- vation contributes to the overall rate-determining barrier.
Overall, the C2–H bond cyanation of indole with NCTS cata- lyzed by the Rh(III)-complex is exergonic by 9.7 kcal mol−1. The overall activation barrier is 25.6 kcal mol−1. Meanwhile, the sulfonamide group participates in the β-N elimination process via one oxygen atom coordinating to the Rh center.
3.2.2 C7–H cyanation of indole. Except the experimentally observed C2–H bond cyanation of indole with NCTS, we also considered the hypothetical reaction of pyrimidine directed indole with NCTS involving C7–H bond cyanation, which was not experimentally observed. According to the mechanism pre- sented in Scheme 1 (left-hand side), the free energy profile shown in Fig. 2 for the C7–H bond cyanation of indole with NCTS has been calculated. First, through a ligand exchange between the pyrimidine directed indole and NCTS to give intermediate 1a, and then it isomerizes to intermediate 10a, which is a precursor for the C7–H bond activation (Fig. 2a). From 10a, the proton at the C7 position can be deprotonated under the assistance of the acetate anion through a six- membered ring transition state TS10a to afford a six-mem- bered rhodacycle intermediate 12a. Subsequently, one mole- cule of substrate NCTS comes in and coordinates with the Rh center using the terminal nitrogen atom to yield intermediate 13a. From intermediate 13a, the cyano group inserts into the Rh-C7 bond via a four-membered ring transition state TS13a to generate an eight-membered ring intermediate 14a with an activation barrier of 25.6 kcal mol−1 (13a → TS13a). Next, release of the hypothetical product P2 from intermediate 15a through the β-N elimination process gives intermediate 8a. Finally, the protonation of 8a is the same as the aforemen- tioned C2–H bond cyanation reaction (Fig. 1b).
As shown in Fig. 2, the insertion step of the cyano group into Rh–C7 bonds is the rate-determining step for C7–H cyana- tion of indole with NCTS. Because there is a more stable inter- mediate (5a) in the C2–H cyanation pathway and the first step of C–H activation is reversible, the C7–H cyanation also needs to pass the more stable intermediate (5a). Thus, the overall activation barrier for C7–H cyanation of indole with NCTS is 29.0 kcal mol−1 (5a → TS13a).
3.2.3. Comparison between C2–H and C7–H cyanation of indole. Comparing Fig. 1 with Fig. 2, it can be found that the overall activation barrier of C7–H bond cyanation is higher than that of C2–H bond cyanation by 3.4 kcal mol−1. These cal- culation results are in good agreement with the experimental observations that there was only C2–H cyanation for the pyri- midine directed indole. The reason for this phenomenon might be due to the different nucleophilic ability of C–Rh(III) bonds; the electron density of C2 in heterocyclic structure 5a by NBO analysis is −1.154, which is much larger than that of C7 in structure 13a (−0.373). In structure 5a, the lone-pair elec- tron of N atoms can increase the electron density of this ring through delocalization, and thus C2 has much stronger nucleophilicity than C7 in the indole substrate.
3.3 C–H cyanation of indoline with NCTS
As mentioned in the Introduction, when the substrate is indo- line, C7–H bond cyanation instead of C2–H bond cyanation was experimentally observed. C7–H cyanation of indoline. Similar to the C–H bond cyanation of indole, there are two possibilities of C–H cyanation of indoline with NCTS, C7–H cyanation and C2–H cyana- tion. Here, we first discuss the C7–H cyanation of indoline with NCTS. On the basis of a similar mechanism shown in Scheme 1 (left-hand side), Fig. 3 shows the energy profile cal- culated for the C7–H cyanation of indoline. As shown in Fig. 3, before C7–H bond activation, 1c must exchange its coordinat- ing substrate NCTS with indoline to form the carbonyl co- ordinated complex 2b. Then the intermediate 2b undergoes a concerted deprotonation and metalation process (assisted by
−OAc) through a six-membered ring transition state TS2b and a dissociation of one molecule of HOAc to generate a six- membered metallacycle 4b with 16-electron coordination. The free energy barrier of this step is 20.9 kcal mol−1.
Next, let us discuss the cyano group insertion and β-N elim- ination steps. The cyano group insertion step starts with the coordination of NCTS to the Rh center of the intermediate 4b via the transition state TS4b. This process generates an 18-elec- tron piano stool structure intermediate 5b. After that, 5b undergoes cyano group insertion into the C–Rh bond via a four-membered ring transition state TS5b to give species 6b. The overall activation barrier for this step is 26.5 kcal mol−1 (1c → TS5b). Then the intermediate 6b isomerizes to one oxygen atom of sulfonamide coordinated complex 7b via the transition state TS6b with an energy barrier of 6.8 kcal mol−1. Subsequently β-N elimination from 7b affords a sulfonamide rhodium intermediate 8a and release of product P3 via tran- sition state TS7b with an activation barrier of 26.1 kcal mol−1. The final step of the catalytic cycle is the protonation of 8a, which is the same as the aforementioned C2–H bond cyana- tion of indole.
Based on the above calculation results, it can be found that the overall activation barrier is 26.5 kcal mol−1 and the overall reaction is exergonic by 10.5 kcal mol−1 for the C7–H bond cya- nation of indoline.
3.3.2 C2–H cyanation of indoline. Now, let us consider another hypothetic reaction of C2–H cyanation of indoline with NCTS, which was not experimentally observed. On the basis of the similar mechanism shown in Scheme 1 (right- hand side), we calculated the free energy profile shown in Fig. 4 for the C2–H cyanation of carbonyl directed indoline with NCTS. Similar to the mechanism previously presented in the C7–H cyanation of indoline, the first step is also the C–H bond activation via the transition state TS1b to afford a five- membered ring intermediate 9b with a barrier of 32.8 kcal mol−1, and then it undergoes an insertion of the cyano group into the C(sp3)–Rh bond through a four-mem- bered ring transition state TS10b to give intermediate 11b with a very high activation barrier of 45.3 kcal mol−1. Next, inter- mediate 11b isomerizes to one oxygen atom of the sulfona- mide group coordinated intermediate 12b followed by β-N elimination to afford the product and release of intermediate 8a. The barrier for this step is 18.8 kcal mol−1. Finally, the pro- tonation of 8a by one molecule of HOAc and re-coordination with NCTS realize the regeneration of the active species 1c and completion of the catalytic cycle, which is the same as the aforementioned C2–H bond cyanation of indole with NCTS.
3.3.3 Comparison between C2–H and C7–H cyanation of indoline. Comparing the energy profiles of the C2–H cyanation and C7–H cyanation of indoline, it can be found that the overall activation barrier for the C7–H bond cyanation is 26.5 kcal mol−1, which is much lower than the barrier of C2–H bond activation of indoline (32.8 kcal mol−1). Moreover, the overall activation barrier of C2–H bond cyanation is up to 45.3 kcal mol−1. Therefore, C7–H bond cyanation is kinetically much more favorable than C2–H bond cyanation. These computational results are in good agreement with experimental observations. The reason for this phenomenon can be attribu- ted to the different hybridization platforms of the carbon involved in the C–H activation step.
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