Mechanism, regioselectivity and stereoselectivity of NHC-catalyzed [12+2] annulation of 5H-benzo[a]-pyrrolizine-3-carbaldehydes and cyclic sulfonic imines: a DFT study

Abstract

The mechanism, regioselectivity and enantioselectivity of the [12+2] cyclization reaction between 5H-benzo[a]-pyrrolizine-3-carbaldehydes and cyclic sulfonic imines catalyzed by triazolium-derived N-heterocyclic carbene (NHC) have been elucidated by density functional theory calculations. The optimal reaction pathway occurs in seven steps: nucleophilic addition, proton transfer assisted by HOAc, oxidation, deprotonation, Michael addition leading to the formation of a new C–C bond, ring closure leading to the formation of a new C–N bond, and catalyst regeneration yielding the target product. The DFT results indicate that the fifth step is the stereo-controlling step, and SR-piperazin-2-one is the dominant product. The calculated enantiomeric excess (93.4% ee) agrees well with the experimental findings (95% ee). Analysis of the distortion-interaction shows that the stronger interaction energy and smaller distortion energy are the main factors determining the reaction's stereoselectivity. Analysis of the global reactivity index suggests that the role of NHC is to enhance the nucleophilicity of the substrate 5H-benzo[a]pyrrolizine-3-carboxaldehydes, thereby facilitating further reactions.

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1. Introduction

Piperazines, especially piperazin-2-ones, are often found in drug molecules^1–4 due to their favorable pharmacokinetic profile.^5,6 For instance, prazosin is the active component of the antihypertensive drug furazolidone.⁷ Aripiprazole, which is used to treat schizophrenia, also contains piperazine substructures.^8,9 Nalidixic acid, a widely used antibiotic to treat bacterial infections, also features a piperazine moiety in its active center (Scheme 1).^10–13 Over the past few years, several methods have been reported in search of new techniques for efficient synthesis of piperidin-2-ones. However, these methods rely on transition metal catalysis, and the reactions need to be carried out at high temperatures.^14,15 Therefore, developing efficient and environmentally friendly methods to synthesize piperazin-2-one remains a desirable yet challenging task.

Scheme 1 Representative drugs containing piperazin-2-one.

As a unique class of organocatalysts,^16,17 N-heterocyclic carbenes (NHCs) exhibit essential catalytic functions in various chemical transformations. In general, when NHC reacts with aldehydes, the polarity of the aldehydes is reversed, and the nucleophilic intermediates formed are capable of reacting with electrophilic reagents, thus facilitating a wide range of transformations, such as cycloaddition,^18,19 C–C bond activation,^20–22 cross-coupling,^23,24etc. Cycloaddition reactions such as [2+2],^25,26 [3+2],^27–29 [3+3],^30,31 [4+2],^32–34 and [4+3]^35,36 have received much attention in recent years.^37–40 In particular, NHC-catalyzed asymmetric [12+2] cycloaddition reactions have been widely used to synthesize compounds with polycyclic rings.

Recently, the Qi group⁴¹ reported a chiral NHC catalyzed reaction of 5H-benzo[a]-pyrrolizine-3-carbaldehydes and cyclic sulfonic imines towards polycyclic piperazin-2-ones. When THF was used as a solvent and KOAc as a base, the polycyclic piperazin-2-ones were obtained with high yield and stereoselectivity. Detailed experimental information is shown in Scheme 2. Although the experimental results of Qi's group are instructive, the detailed reaction mechanism is still unclear. There are some uncertainties about the reaction. For example, 5H-benzo[a]pyrrolizine-3-carbaldehyde is activated by the catalyst NHC, but how does this process occur? The polycyclic piperazin-2-ones with SR-configuration were suggested to be the major product. What factors govern stereochemical outcomes? What role does the catalyst play throughout the entire reaction process? In this paper, a theoretical study was carried out on the catalytic reaction, and we aim to address the questions raised and elucidate the detailed reaction mechanism.

Scheme 2 Reaction model for the synthesis of piperazin-2-ones.

2. Computational details

All quantum chemical calculations were performed using density functional theory (DFT) implemented in the Gaussian 16 (Rev. A03) software package.⁴² M06-2X has been demonstrated to perform well in catalytic reactions such as organocatalysis^43–47 and transition metal catalysis.^48–52 All stationary points, including transition states and intermediates, were optimized using the M06-2X^53–55 functional and the 6-31G(d,p) basis set. The IEF-PCM^56,57 was chosen to simulate the solvent effects of THF. Subsequent frequency analyses conducted at the same computational level revealed the presence of a single imaginary frequency for all transition states, and there are no imaginary frequencies for intermediates, products, and reactants. In order to validate the connection of each transition state with the relevant intermediates, intrinsic reaction coordinate^58,59 analysis was conducted. Based on the optimized structures, single-point energy calculations were performed at the IEF-PCM(THF)M06-2X-D3/6-311++G (2df, 2dp) level.

To test the reliability of the computational level, we chose other DFT methods (ωB97X-D⁶⁰), the basis set 6-311++G(d,p), and the solvation model SMD⁶¹ to perform energy calculations for the transition states in the stereoselectivity-determining step (see Tables S1 and S2, for details, SI). We used the CYLview⁶² software to demonstrate the optimized geometries.

3. Results and discussion

3.1. Reaction mechanism

Based on the experimental data of the Qi group⁴¹ and our theoretical computations, we establish a catalytic cycle for the NHC-mediated [12+2] annulation between 5H-benzo[a]-pyrrolizine-3-carbaldehyde (R1) and cyclic sulfonic imine (R2) (Scheme 3). In the initial stage, the acetate ion (OAc⁻) deprotonates the pre-NHC, generating the active NHC and acetic acid (HOAc) (see Fig. S1, SI). The catalytic cycle consists of seven steps as follows: (1) the intermediate M1 is formed by the nucleophilic attack of the NHC on substrate R1, (2) the Breslow intermediate M2 is produced by 1,2-proton migration, (3) M2 is transformed into intermediate M3 by oxidative transformation, (4) M4 is formed through deprotonation, (5) M5 is produced by Michael addition of M4 to cyclic sulfonic imine R2, (6) ring closure, and (7) the target product P is generated with the regeneration of the catalyst. The mechanism is analyzed in the next section.

Scheme 3 The possible catalytic cycle for [12+2] cyclization.

3.1.1. Step I: nucleophilic addition. NHC undergoes nucleophilic addition with substrate R1via transition states re/si-TS1 to generate intermediates re/si-M1. The activation barriers for si-TS1 and re-TS1 were determined to be 15.5 and 15.2 kcal mol⁻¹, respectively, as illustrated in Fig. 1. The relative energies for intermediates re-M1 and si-M1 were calculated to be 9.1 and 9.9 kcal mol⁻¹. It should be noted that conformational searches for re/si-TS1 and re/si-M1 were performed, and the structures in Fig. 1 are the most stable (see Table S3, SI). The C1–C2 bond distance is shortened from 2.02 Å (re-TS1) and 2.00 Å (si-TS1) in the transition states to 1.56 Å (re-M1) and 1.55 Å (si-M1) in the intermediates, as shown in Fig. 2, indicating complete coordination between the catalyst and substrate.

Fig. 1 Free energy profile (kcal mol⁻¹) for the [12+2] annulation reaction catalyzed by NHC.

Fig. 2 Optimized intermediate and transition state geometries (distance in Å).

3.1.2. Step 2: 1,2-proton transfer. The second step of the reaction is proton transfer from C2 to O4. There are three possible pathways for this step (Scheme 4). Computational analysis of the direct proton transfer route revealed extremely high activation barriers (51.8 kcal mol⁻¹ for re-TS2^D and 45.4 kcal mol⁻¹ for si-TS2^D, Fig. S2, SI), which ruled out the feasibility of this path. The OAc⁻-assisted proton transfer pathway proceeds via transition states re/si-TS2^B and the activation barriers are calculated to be 26.4 kcal mol⁻¹viare-TS2^B and 28.6 kcal mol⁻¹viasi-TS2^B. Finally, we explored the proton transfer process with the presence of HOAc. As shown in Scheme 4, in the presence of HOAc, the activation barrier of the proton transfer (6.9/10.0 kcal mol⁻¹viare/si-TS2, Fig. 1) was significantly reduced compared to that of the direct or OAc⁻-mediated mechanism. It is clear that HOAc facilitates the proton transfer process. In addition, the activation barrier of re-TS2 is lower than that of si-TS2 by 3.1 kcal mol⁻¹; therefore, the re-face is more feasible, and the subsequent discussion is only for re-M2.

Scheme 4 Possible paths for M1 → M2 conversion.

3.1.3. Step 3: oxidation process. The third step is oxidation of the intermediate M2 through the hydride transfer to oxygen (HTO), which has been generally proven to be the most efficient pathway in previous theoretical studies.^63–65 According to Fig. 1, the transfer of hydride H4 from M2 to 3,3′,5,5′-tetra-tert-butyl diphenoquinone (DQ) generates intermediate M3via the transition state TS3. This process requires overcoming an activation barrier of 4.5 kcal mol⁻¹. Fig. 2 shows that the O4–H5 bond in TS3 (1.09 Å) is elongated by 0.12 Å relative to M2 (0.97 Å).

3.1.4. Step 4: deprotonation process. In the fourth step of the catalytic cycle, intermediate M3 undergoes deprotonation to form M4. As shown in Scheme 5, two possible reaction routes were considered. In path a, the proton H10 of intermediate M3 is seized by OAc⁻ to produce intermediate M4via the transition state TS4^B. As shown in Fig. 3, the activation barrier of TS4^B is 7.9 kcal mol⁻¹. In path b, the proton H10 of intermediate M3 is abstracted by [DQH]⁻ and a 1.3 (TS4) kcal mol⁻¹ barrier is needed for the transformation from intermediate M3 to TS4. It is obvious that TS4 is 6.6 kcal mol⁻¹ lower than TS4^B, making the [DQH]⁻-mediated deprotonation process more feasible.

Scheme 5 Two possible pathways for M3 → M4 conversion.

Fig. 3 Energy profile for step 4. The relative energies and distances are given in kcal mol⁻¹ and Å, respectively.

3.1.5. Step 5: addition of M4 to R2. In this step, the C8 atom of R2 attacks the C7 atom of M4 generating four intermediates (M5RR, M5RS, M5SR and M5SS) as the re/si face of R2 can attack the re/si face of M4. Fig. 4 shows the four addition modes between M4 and R2: re–re, re–si, si–re, and si–si. It is noteworthy that TS5 (RR/RS/SR/SS) in Fig. 1 has the lowest relative energy, which has been confirmed by a systematic conformational search (see Fig. S3 and Table S4, SI). As can be seen from Fig. 1, the activation barriers of TS5RR, TS5RS, TS5SR and TS5SS are 6.7, 6.6, 4.6 and 6.2 kcal mol⁻¹, respectively. By comparison, we observed that TS5SR has the lowest activation barrier, so the most feasible route for the addition of R2 to M4 is that viaTS5SR and generating the intermediate M5SR. For simplicity, the discussion in the main paper is limited to the transformation pathways of M5SR. The remaining three pathways are shown in Fig. S4 (SI). As shown in Fig. 2, the length of the C7–C8 bond in M5SR is decreased by 0.65 Å compared to TS5SR.

Fig. 4 Four configurations for the reaction of M4 with R2.

3.1.6. Step 6: ring closure. In this step, the N9 atom of M5SR attacks the C2 atom to generate the 6-membered cyclic intermediate M6SR through the transition state TS6SR. An activation barrier of 10.3 kcal mol⁻¹ needs to be crossed in this process (Fig. 1). The C2–N9 bond contracts from 1.76 Å in TS6SR to 1.59 Å in M6SR (Fig. 2).

In addition to the [12+2] cycloaddition discussed above, we also considered the [3+2] cycloaddition, in which the N9 atom attacks the C6 atom forming the five-membered ring intermediate M6′. According to our calculations, the activation barrier for this process is calculated to be at least 34.2 kcal mol⁻¹. Therefore, the [3+2] cycloaddition is difficult to occur under experimental conditions, and thus can be ruled out (see Fig. S5 for details, SI).

3.1.7. Step 7: release of the NHC catalyst. In the last step of the catalytic cycle, the NHC dissociates from the intermediate M6SRvia the transition state TS7SR generating the final product PSR and the catalyst is regenerated. The activation barrier calculated for this process is 10.8 kcal mol⁻¹ (Fig. 1). As shown in Fig. 2, for the transformation of M6SR → TS7SR, the C1–C2 bond is elongated by 0.64 Å (1.58 → 2.22 Å).

3.2. Other regioselective reaction pathways

For the reaction between M4 and R2, in addition to forming intermediate M5SR with a new C7–C8 bond as discussed above. We also examined the formation pathway of intermediate M5SR', in which the C8 atom of R2 attacks the C2 atom of M4SR. It can be seen from Fig. S6(SI) that a 45.8 kcal mol⁻¹ activation barrier needs to be overcome in this process. This value was significantly higher than that of TS5SR (ΔG = 4.6 kcal mol⁻¹). Therefore, C7–C8 bond formation is more preferred than C2–C8 bond formation.

To explore the origin of the regioselectivity, Parr function analysis⁶⁶ was performed. As shown in Table 1, the nucleophilic P⁻_k value of the C7 atom is 0.560, much larger than 0.054 for the C2 atom. Thus, the electrophilic C8 atom reacts preferentially with the C7 atom, consistent with our calculations and experimental observations.

Table 1 Electrophilic (P⁺_k) and nucleophilic (P⁻_k) Parr functions for C2 and C7 in M4 and C8 in R2

	M4		R2
	C2	C7	C8
P ^+ k	0.189	0.082	0.276
P ^− k	0.054	0.560	−0.043

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3.3. Origin of stereoselectivity

As discussed above, the addition of M4 to R2 generating intermediates M5RR, M5RS, M5SR, and M5SS is the stereoselectivity-determining step. The activation barriers calculated for TS5RR, TS5RS, TS5SR, and TS5SS are 6.7, 6.6, 4.6, and 6.2 kcal mol⁻¹, respectively. The activation barrier difference between TS5SR and TS5RS is 2.0 kcal mol⁻¹, corresponding to 93.4% enantiomeric excess (ee). Our result agrees well with the experimental result (95% ee).⁴¹

To understand the origin of the stereoselectivity, we performed distortion-interaction analysis⁶⁷ of TS5(RR/RS/SR/SS) (Table 2). Although TS5RS/SR has larger distortion energies than TS5RR/SS, their interaction energies are much stronger. As for TS5RS and TS5SR, they have similar interaction energies, but TS5SR exhibits a smaller distortion energy, which should be the reason for its lower activation barrier.

Table 2 Distortion/interaction analysis for stereoselective transition states (unit: kcal mol⁻¹)

Species
TS5(RR)	6.65	5.44	12.09	−24.56
TS5(SS)	6.18	5.59	11.77	−26.65
TS5(RS)	8.48	13.90	22.39	−38.54
TS5(SR)	7.86	13.44	21.30	−38.16

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3.4. Effect of substituents

In experiments, the aldehydes with electron-donating groups at the benzene rings gave lower yields compared with those with no substituent (entries 1–3). In addition, the cyclic sulfonic imines with electron-donating groups led to good yields (entries 4–5). To get a better understanding of this result, we performed additional calculations for the rate-determining step [RDS, M5SR → TS7SR]. As summarized in Table 3, entries 2 and 3 have higher activation barriers (22.3 and 23.0 kcal mol⁻¹) compared to entries 1, 4 and 5 (20.4/19.5 and 19.4 kcal mol⁻¹). This agrees well with the yields reported in experiments.

Table 3 Activation barriers for the conversion of M5(SR) → TS7(SR) with different substituents

Entry	R^1	R^2	ΔG^‡ (kcal mol^−1)	Yield (%) in experiment
1	H	H	20.4	78
2	CH(CH3)2	H	22.3	65
3	CH3O	H	23.0	49
4	H	CH3	19.5	85
5	H	CH3O	19.4	89

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3.5. The role of the catalyst

To learn more about the role that the catalyst plays in this process, global reactivity index (GRI) analysis^68–72 was performed. As shown in Table 4, the nucleophilicity (N) increases from 3.347 eV for R1 to 4.075 eV for re-M1 and then to 4.956 eV for M2. These results indicate that the nucleophilicity of R1 is significantly enhanced. Although intermediate M3 becomes less nucleophilic after an oxidative process, the subsequent deprotonation generates an even more nucleophilic intermediate M4 (5.132 eV). In summary, the role of the catalyst is to increase the nucleophilicity of R1, thereby facilitating further reaction with R2.

Table 4 Electronic potential (μ, in a.u.), chemical hardness (η, in a.u.), global electrophilicity (ω, in eV), and global nucleophilicity (N, in eV) of reactants R1 and R2 and some intermediates

Species	η	μ	ω	N
R1	0.237	−0.137	1.083	3.347
re-M1	0.233	−0.112	0.737	4.075
re-M2	0.204	−0.094	0.592	4.956
M3	0.208	−0.181	2.134	2.561
M4	0.166	−0.107	0.936	5.132
R2	0.255	−0.206	2.259	1.239

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4. Conclusion

The [12+2] cycloaddition of 5H-benzo[a]pyrrolizine-3-carboxaldehyde R1 with cyclic sulfonate imine R2 catalyzed by NHC was investigated using density-functional theory (DFT) calculations in order to elucidate the reaction mechanism, regioselectivity and stereoselectivity. The most preferred mechanism involves seven steps: the NHC undergoes nucleophilic attack on the re-face of R1, HOAc-mediated proton transfer, DQ-driven oxidation, [DQH]⁻ mediated deprotonation, Michael addition, ring closure and catalyst regeneration to yield piperazin-2-ones. The fifth step determines the stereoselectivity and preferentially leads to the SR configurational product. The calculated enantiomeric excess (93.4% ee) agrees well with the experimental findings (95% ee). GRI analysis demonstrates that the catalyst enhanced the nucleophilicity of R1, thus facilitating the subsequent reaction with R2.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

Data will be made available on request.

Supplementary information: Computational details, additional computational results, and Cartesian coordinates of all the stationary points in the reactions. See DOI: https://doi.org/10.1039/d5nj02133b

Acknowledgements

DFT computations were carried out on the cluster at USTL.

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