New routes towards azomethine ylide generation from prolines to synthesize diverse N-heterocycles: a DFT supported endo-selective mechanism†

Radha M. Laha‡ ^ab, Shobhon Aich‡^a, Ankan Kumar Sarkar^c, Tanmoy Dutta^d, Narendra Nath Ghosh^e, Saikat Khamarui*^f and Dilip K. Maiti*^a
aDepartment of Chemistry, University of Calcutta, 92 A. P. C. Road, Kolkata-700009, India. E-mail: dkmchem@caluniv.ac.in
^bDepartment of Science & Humanities, Murshidabad Institute of Technology, West Bengal-742102, India
^cSchool of Material Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
^dDepartment of Chemistry, JIS College of Engineering, Kalyani, West Bengal 741235, India
^eDepartment of Chemistry, Pakuahat A.N.M. High School, Malda, West Bengal 732138, India
^fDepartment of Chemistry, Government General Degree College at Kalna-1, Purba Bardhhaman, 713405, India. E-mail: saikatkhamarui21@gmail.com

First published on 14th August 2024

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Introduction

The catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with activated olefins has emerged as a highly valuable and firmly established approach for preparing enantio-enriched substituted N-heterocycles such as pyrrolidines and pyrrolizines.^1,2 Pyrrolidines are important bioactive scaffolds³ with medicinal properties, including HIV inhibition and antifungal, antibacterial, and antithrombotic activities.^4–6 Structurally diverse pyrrolizine derivatives are found in many natural products and exhibit a range of bioactivities, making them attractive to chemists.⁷ Building upon the earlier work of Grigg and colleagues,⁸ who employed stoichiometric amounts of metal salts and an ephedrine derivative as a chiral ligand, the research groups of Zhang⁹ (utilizing a chiral Ag complex) and Jørgensen¹⁰ (employing a Zn-based chiral Lewis acid) independently reported the initial instances of catalytic enantioselective 1,3-dipolar cycloaddition using azomethine ylides derived from imino-esters and activated olefins. This process's remarkable efficacy relies on the generation of a metalated azomethine ylide through the coordination of the nitrogen and oxygen atoms to the metal. The decarboxylative generation of azomethine ylides from amino acids and carbonyl compounds has been extensively investigated by Rizzi¹¹ and others,¹² including reports utilizing copper catalysts¹³ and NHC-gold(I) complexes.¹⁴ Recently, we presented the formation of stable azomethine ylides from L-proline and phenyl glyoxal, followed by their 1,3-dipolar cycloaddition to produce fused N-heterocycles.¹⁵ Li et al. and others reported the copper-catalyzed oxidative synthesis of azomethine ylides from L-prolines and aldehydes, alcohols, or benzyl halides.¹⁶

We now aim to broaden the scope of azomethine ylide formation by using L-proline and β-nitrostyrene with benzylamine as an organocatalyst and achieving redox neutrality and accessibility. Herein, we present our preliminary findings on the benzylamine-catalyzed generation of azomethine ylides using proline and β-nitrostyrene (eqn (iii), Scheme 1) as well as another protocol involving proline and benzylamine as substrates (eqn (iv), Scheme 1). This reactive intermediate (1,3-dipole) has been captured using common organic techniques, including intermolecular [3 + 2]-cycloaddition reactions with electron-deficient alkenes, C–C coupling with alkynes, and ring annulation reactions to form valuable fused N-heterocycles. Through this regio- and stereo-selective pathway, several new bonds and chiral centers have been formed, highlighting the significance of the decarboxylative C–C and C–N coupling reactions as powerful synthetic tools due to their efficiency, selectivity, and convenience.

Results and discussion

Our investigation began with the reaction involving L-proline (1a, 1 mmol) and β-nitrostyrene (3a, 1 mmol) and a catalytic amount of CuBr (5 mol%) in toluene under reflux conditions. Initially, no product (6a) was obtained (Table 1, entries 1 and 2 and Scheme 2).

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To enhance the yield, we employed various metal catalysts such as AuCl, AgOTf, Ir(cod)Cl, and FeCl₃ (entries 3–6, Scheme 2); unfortunately, none of them afforded 6a. Interestingly, when 1.0 equiv. of L-proline (1a), 0.1 equiv. of benzyl amine (2a), and 2.0 equiv. of β-nitrostyrene (3a) were heated in toluene at 130 °C, we exclusively obtained 6a without the presence of any metal salt (entry 12, Scheme 2). Moreover, we observed that the absence of 2a during the reaction (Table 1, entry 10 and Scheme 2) prevented the formation of 6a. The use of (S)-(−)-1-phenylethylamine, a chiral base, did not impact the yield and chiral induction of product 6a (entry 14, Table 1 and Scheme 2). Using a strong base like triethylamine instead of 2a did not improve the yield of 6a (entry 15, Table 1 and Scheme 2).

In another experiment, when 1a and 2a were employed with phenyl acetylene (4a), surprisingly, we achieved a good yield of 7a (65%) with CuBr (Table 1, entry 1 and Scheme 3) compared with other metal salts (entries 2–6, Scheme 3) under aerobic conditions. Without a metal catalyst, no conversion was found (entry 10, Scheme 3). As shown in Schemes 2 and 3, toluene under reflux conditions proved to be the most effective solvent compared to other organic solvents such as CH₃CN, CH₂Cl₂, and THF (Table 1, entries 7–9, 11, and 13).

Under the optimized conditions established for the smooth decarboxylative formation of azomethine ylide via an organocatalytic pathway (Scheme 2), we also observed the simultaneous grafting of this intermediate with another molecule of β-nitro styrene (3). The resulting [3 + 2] cycloaddition reaction yielded 1-nitro-2,3-diaryl-hexahydro-pyrrolizines (6), as shown in Scheme 4. Because of the high electron deficiency of β-nitro styrene, other common electrophiles did not participate in the [3 + 2] cycloaddition with the in situ generated azomethine ylide. However, when we used maleimide (a very good Michael acceptor), we observed a mixture of products in very poor yield, possibly due to the formation of a Michael adduct between maleimide and L-proline. To investigate the general feasibility of this organocatalytic process, we employed differently substituted β-nitro styrenes while keeping the proline part constant. As expected, methyl (6b, 6h), alkoxy (6c, 6d), halogen (6e, 6f–g), and naphthyl (6i) functionalities were well tolerated under the developed reaction conditions, along with the unsubstituted variety (6a). Using piperidine-2-carboxylic acid instead of L-proline also produced the corresponding octahydro-indolizine derivative (6j). Since azomethine ylide is an achiral and planar intermediate, racemized products (6a–j) were obtained with L-proline. Good yields (60–70%) and a moderate reaction time (8h) have been observed for this developed reaction. Finally, the regio- and stereoselectivity of compound 6g were established based on previous literature and NOESY spectra (ESI†).

By switching to the concept of organocatalysis and introducing benzylamines as components for azomethine ylide development in the presence of an oxidant (Scheme 3), the substrate scope for trapping the azomethine ylide has been expanded. The decarboxylative C–N and Csp³–Csp coupling reactions showcased the versatility of this method in the presence of CuBr (5 mol%) and aerobic conditions, as shown in Scheme 5. Various benzylamines and alkynes were employed under the optimized conditions. The results indicate successful reactions with unsubstituted benzylamines (7a–c, 7h, and 7i) as well as those substituted with electron-withdrawing groups such as nitro (7d and 7k), chloro (7f), and fluoro (7e, 7g, and 7j). In terms of aromatic alkynes, the reaction proceeded well with unsubstituted varieties (7a, 7d, and 7e), as well as those with methyl substituents (7b, 7f, and 7g) and methoxy groups (7c and 7h–k). Additionally, the reaction showed success with substrates containing biphenyl rings (7i) and naphthyl moieties (7h–k). The corresponding 1-benzyl-2-arylethynyl-pyrrolidine derivatives (7a–k) along with 1-(4-methoxybenzyl)-2-(phenylethynyl)piperidine (7l) were obtained in moderate to good yields (53–63%) within a reasonable time frame of 9–12 h. However, it should be noted that the use of electronically activated benzylamines bearing an electron-donating group did not yield the desired product 7.

Electron-rich aromatic nuclei underwent C–C coupling with Cu-chelated alkynes to form fused polynuclear-N-heterocycles with an exocyclic double bond (8, Scheme 6) under prolonged heating. Therefore, L-proline (1a), 4-methylbenzylamine (2e), and various terminal alkynes (4) led to the synthesis of the corresponding products 8a–c in good yields (50–60%). Furthermore, naphthylbenzylamine also afforded product 8d in 55% yield following the same protocol. It is worth noting that the choice of different alkynes does not pose any barriers to obtaining the cyclized product 8. All synthesized products were characterized using relevant spectroscopic analyses (ESI†).

To trap the intermediate, a three-component coupling reaction was conducted using an electron-deficient olefin, leading to the formation of substituted hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-diones (9) and hexahydro-pyrrolizines (10a–c) (Scheme 7). Piperidine-2-carboxylic acid also smoothly formed the azomethine ylide, yielding a subsequent cycloadduct (10d and e) with maleimide derivatives. The reaction involved 1,3-dipolar cycloaddition of azomethine ylide intermediates derived from L-proline and benzyl amines, with N-substituted maleimide, fumarate, and cinnamate. The synthesized products (9a–j and 10a–d) were characterized using spectroscopic analyses, and the structures of 9a and 10e were confirmed via a single crystal XRD study.¹⁷ Lower yields were attributed to the formation of Michael adducts between benzyl amines and maleimides.

Possible mechanistic pathways for the developed reaction procedures have been proposed based on literature reports¹⁸ and present observations (Scheme 8). The organocatalytic pathway involves L-proline (1a) undergoing Michael addition with β-nitrostyrene (3), followed by amine-catalyzed decarboxylation and elimination of CH₃NO₂ leading to the formation of the azomethine ylide intermediate I (eqn (iii), Scheme 1). Another pathway involves the Cu-catalysed aerobic oxidation of benzyl amine into an imine¹⁹ followed by coupling with L-proline (1a), which then undergoes smooth decarboxylation and liberates ammonia to yield the desired intermediate-I (eqn (iv), Scheme 1). Mass analysis was performed by taking aliquots from the reaction mixture from time to time to identify probable intermediate(s) towards azomethine ylide formation in both pathways (Schemes 2 and 3). To our delight, we observed peaks that corresponded to the probable intermediates, as shown in the ESI.† Here, Cu(I) is used to catalyse the oxidation of the amine under aerial O₂¹⁹ and does not play any further role in azomethine ylide formation or the subsequent 1,3-dipolar cycloaddition reaction. The reaction shown in Scheme 3 stops under a N₂ atmosphere.

Various dienophiles, such as β-nitrostyrene (3, Scheme 4), N-substituted maleimide (5a–j), fumarate ester (5k, and 5l), and trans-ethylcinnamate (5m), as shown in Scheme 7, undergo formal 1,3-dipolar cycloaddition with trans-azomethine dipole (I) via endo-TS to synthesize diverse N-heterocycles (6 and 9–10).^18,20 Theoretical DFT calculations show that the regio-isomer reported here (6) is found to be more stable than other possibilities and the endo-TS (6a: 3.074 kcal mol⁻¹ or 0.0049 Hartree; 9a: 3.419 kcal mol⁻¹ or 0.005448 Hartree) is more favourable than the exo-TS (6a: 7.145 kcal mol⁻¹ or 0.011387 Hartree; 9a: 6.203 kcal mol⁻¹ or 0.009885 Hartree). When a terminal alkyne is employed, the azomethine ylide accepts a proton at the benzylic carbon atom and is converted to a simple quaternary imine. Then, nucleophilic addition of Ar₂–CC–Cu species onto the imine takes place to afford the C–C-coupled product 7 (Scheme 5).

All density functional theory (DFT) calculations of this study were performed using the Gaussian 16 program suite with Grimme d3 dispersion correction.^21–23 DFT calculations were performed by considering the model structures of the transition states (TS) for exo, endo (Schemes 4 and 7), and regio products, as shown in Scheme 4. To compare the favorable pathway of the reaction, activation energy was calculated considering the electronic structures of the TS.²⁷ Ground state geometry optimizations for all the reactants, products, and intermediates were performed with the B3LYP functional using the localized 6-31g(d,p) basis set. Previous studies reveal that the dispersion corrected B3LYP level of theory offers precise geometry with satisfactory results for this type of mechanism.²⁸ Solvation was introduced implicitly by applying the Polarizable Continuum Model (PCM),^29,30 using the integral equation formalism variant as implemented in the Gaussian 16 package with toluene as the solvent. In the solution phase, all geometry optimizations were carried out without symmetry restrictions. Thermodynamic parameters like free energy and enthalpy corrections were evaluated at 298.15 K and 1 atm pressure, incorporating zero point energy corrections (ZPE). Vibration frequency calculation at the same level of theory confirmed that the optimized geometries correspond to minima on the potential energy surfaces. Conformational analysis was done by varying the dihedral angle and finding the minimum energy structure. For the TS calculation, the QST3 method was applied and TS structures were confirmed by imaginary frequency analysis.²⁴ Chem3D 16.0 software was used to calculate the steric energies of different TS geometries through MM2 server computations.²⁵

Following significant experimental observations we have performed density functional theory (DFT) calculations to establish the favorable pathway between exo and endo products. The free energy profile for the exo and endo product 6a shown in Scheme 4 is represented in Fig. 1. The optimized geometries of the reactant, product, and corresponding transition states considering both exo and endo pathways are also shown in the same figure. As per the DFT calculations shown in Scheme 4, a higher free energy barrier via a transition state was observed for the exo product (7 kcal mol⁻¹) than for the endo product (3 kcal mol⁻¹). Due to the low free energy barrier via the endo pathway, endo products are predominantly obtained experimentally.

It is well known that typical π–π stacking geometries are known to be energetically favorable.^31,32 Fig. 2 shows the electronic structures of TS considering different possible pathways of the reaction shown in Scheme 4. The low energy barrier for the formation of the endo product comes from the stability of the TS through π–π stacking. Two phenyl rings are 3.9 Å apart from each other in the endo TS whereas they are 4.7 Å apart in the exo TS.³³ The ‘CH–O’ distance in the endo product is less than that in the exo product (Fig. 2). The presence of secondary orbital interaction in the endo TS is also reflected in the endo TS orbital interaction shown in Fig. 2.²⁶ Regio product formation is very difficult as two phenyl rings are in opposite directions in the TS of this pathway (Fig. 2), revealing the least chance of π–π stacking. Considering all the observations, the endo product should be the predominant product, as shown in Scheme 4.³⁴

The same level of theory was used in Scheme 7 (Fig. 3) to identify favorable pathways like the previous one. Free energy calculation reflected that a comparatively stable transition state was obtained for the endo pathway than the exo pathway of product 9a. A lower free energy barrier of 3 kcal mol⁻¹ through the endo pathway than the exo pathway (6 kcal mol⁻¹) is the main reason for the predominant formation of the endo product. As per the MM2 calculation data from Chem3D software, both the endo-TS shown in Schemes 4 and 7 are sterically more stable than the exo-TS considering different energy parameters.²⁵

MM2 server computation:

endo-TS (Scheme 4) — stretch energy: 0.9 kcal mol⁻¹; bend energy: 13 kcal mol⁻¹; stretch bend energy: 0.03 kcal mol⁻¹; torsion energy: −12.24 kcal mol⁻¹; non-1,4 VDW energy: −6.04 kcal mol⁻¹; 1,4 VDW energy: 16.89 kcal mol⁻¹; charge dipole–energy: −3.08 kcal mol⁻¹; dipole–dipole energy: −3.85 kcal mol⁻¹; and total energy: 5.61 kcal mol⁻¹.

exo-TS (Scheme 4) — stretch energy: 0.9 kcal mol⁻¹; bend energy: 13.35 kcal mol⁻¹; stretch bend energy: 0.04 kcal mol⁻¹; torsion energy: −11.7 kcal mol⁻¹; non-1,4 VDW energy: −5.78 kcal mol⁻¹; 1,4 VDW energy: 17.03 kcal mol⁻¹; charge dipole–energy: −3 kcal mol⁻¹; dipole–dipole energy: −3.85 kcal mol⁻¹; and total energy: 6.98 kcal mol⁻¹.

endo-TS (Scheme 7) — stretch energy: 2.72 kcal mol⁻¹; bend energy: 32.04 kcal mol⁻¹; stretch bend energy: −0.03 kcal mol⁻¹; torsion energy: −6.0 kcal mol⁻¹; non-1,4 VDW energy: −0.07 kcal mol⁻¹; 1,4 VDW energy: 18.24 kcal mol⁻¹; charge–dipole energy: −15.27 kcal mol⁻¹; dipole–dipole energy: −2.85 kcal mol⁻¹; and total energy: 28.76 kcal mol⁻¹.

exo-TS (Scheme 7) — stretch energy: 2.72 kcal mol⁻¹; bend energy: 32.04 kcal mol⁻¹; stretch bend energy: −0.025 kcal mol⁻¹; torsion energy: −6.16 kcal mol⁻¹; non-1,4 VDW energy: 0.45 kcal mol⁻¹; 1,4 VDW energy: 18.24 kcal mol⁻¹; charge–dipole energy: −15.38 kcal mol⁻¹; dipole–dipole energy: −2.93 kcal mol⁻¹; and total energy: 29.06 kcal mol⁻¹.

Conclusion

Two new methods have been developed for synthesizing azomethine ylide intermediates from L-proline, offering alternatives to conventional techniques. The first method involves organocatalysis, where L-proline reacts with β-nitrostyrene, followed by a 1,3-dipolar cycloaddition reaction. The second method uses a benzyl amine, which undergoes catalytic oxidation under aerobic conditions and reacts with L-proline, allowing for C–C coupling with aromatic alkynes, ring annulations, and [3 + 2]-cycloadditions with suitable olefins. These methods demonstrate good regio- and stereoselectivity, as supported by DFT studies that show slow and symmetry-controlled transition states. Mass spectrometric analysis was used to identify the reaction intermediates and to propose the mechanism for azomethine ylide formation. These methods contribute to the synthesis of valuable N-heterocycles combined with diverse C–N/C–C coupling and cyclization reactions.

Experimental section

Materials and methods

All reagents were purchased from commercial suppliers and used without further purification unless otherwise specified. Commercially supplied ethyl acetate and petroleum ether were distilled before use. The petroleum ether used in our experiments had a boiling range of 60–80 °C. Column chromatography was performed on silica gel (60–120 mesh, 0.12–0.25 mm). Analytical thin-layer chromatography was performed on 0.25 mm extra-hard silica gel plates with a UV 254 fluorescent indicator. The reported melting points are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded at ambient temperature using 300 and 400 MHz spectrometers. Chemical shifts are reported in ppm from the tetramethylsilane internal reference, and coupling constants are reported in Hz. Proton multiplicities are represented as s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), and m (multiplet). Infrared spectra were recorded on an FT-IR spectrometer in thin films. HR-MS data were acquired by electron spray ionization on a Q-ToF-micro quadruple mass spectrometer. Optical rotation of the chiral compounds was measured on a polarimeter using a standard 10 cm quartz cell in a sodium-D lamp at ambient temperature.

General procedure for the synthesis of hexahydro-pyrrolizines (6a–i)

L-Proline (1, 1.0 mmol) and β-nitrostyrene (3, 2.2 mmol) were taken in a dry 25 mL RB flask and 10 mL dry toluene was poured into it. Then a very small amount (10 mol%) of benzyl amine (2a) was added and allowed to reflux under stirring conditions. The progress of the reaction was monitored by thin-layer chromatography (TLC). Toluene was removed from the post-reaction mixture through suction at low pressure and high temperature. It was extracted with ethyl acetate (2 × 10 mL). The combined organic layer was washed with water (3 × 10 mL) and brine (1 × 10 mL). It was then dried over anhydrous Na₂SO₄, filtered, and evaporated using a rotary evaporator under reduced pressure at room temperature. Purification by column chromatography on silica gel (60–120 mesh) with ethyl acetate–hexane (v/v = 1:19) as the eluent afforded the corresponding hexahydro-pyrrolizines 6a–f. All the synthesized compounds were fully characterized using appropriate spectral analyses.

Characterization data of the synthesized hexahydro-1H-pyrrolizines (6a–j)

General procedure for the synthesis of n-benzyl-2-arylethynyl-pyrrolidines/piperidine (7a–l) and extended ring annulations (8a–d)

L-Proline (1, 1.0 mmol) and aliphatic amine (2, 1.2 mmol) were added to a 25 mL RB flask containing 10 mL dry toluene and allowed to reflux for 30 min at 130 °C in the presence of a catalytic amount (5 mol%) of CuBr. Terminal alkyne 4 (1 mmol) was added to the reaction mixture under hot conditions and heating was continued with stirring. The progress of the reaction was monitored by thin-layer chromatography (TLC). We observed the formation of several spots during heating. Under prolonged heating (∼24 h), some of these spots transformed into another new spot. The post-reaction mixture was filtered through a Celite bed in the sintered funnel and the solvent was removed. Then the crude product was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with water (3 × 10 mL) and brine (1 × 10 mL). It was then dried over anhydrous Na₂SO₄, filtered, and evaporated using a rotary evaporator under reduced pressure at room temperature. Purification by column chromatography on silica gel (60–120 mesh) with ethyl acetate–hexane (v/v = 1:9) as an eluent afforded the corresponding N-benzyl-2-arylethynyl-pyrrolidines/piperdines (7a–l) and hexahydropyrrolo[1,2-b]isoquinolines (8a–d). All the synthesized compounds were fully characterized using relevant spectral analyses.

Characterization data of the synthesized n-benzyl-2-arylethynyl-pyrrolidines/piperidines (7a–l) and extended ring annulations (8a–d)

General procedure for the synthesis of hexahydropyrrolo[3,4-a]pyrrolizine-1,3-diones (9a–j) and hexahydropyrrolizines (10a–c) and octahydropyrrolo[3,4-a]indolizine-1,3(2H)-dione (10d)

Proline (1, 1.0 mmol) and aliphatic amine (2, 1.2 mmol) were added to a 25 mL RB flask containing 10 mL dry toluene and allowed to reflux for 30 min at 130 °C in the presence of a catalytic amount (5 mol%) of CuBr. The electron-deficient alkene 5 (1 mmol) was added to the reaction mixture under hot conditions and heating was continued with stirring. The progress of the reaction was monitored by thin layer chromatography (TLC). The post-reaction mixture was filtered through a Celite bed in the sintered funnel and the solvent was removed. Then the crude product was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with water (3 × 10 mL) and brine (1 × 10 mL). It was then dried over anhydrous Na₂SO₄, filtered, and evaporated using a rotary evaporator under reduced pressure at room temperature. Purification by column chromatography on silica gel (60–120 mesh) with ethyl acetate–hexane (v/v = 1:9) as the eluent afforded the corresponding hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-diones (9a–j) and hexahydro-pyrrolizines (10a–c) and octahydropyrrolo[3,4-a]indolizine-1,3(2H)-dione (10d). All the synthesized compounds were fully characterized using appropriate spectral analyses. The structure of 9a was confirmed using single crystal XRD analyses.

Characterization data of the synthesized hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-diones (9a–j) and hexahydro-pyrrolizines (10a–c) and octahydropyrrolo[3,4-a]indolizine-1,3(2H)-dione (10d–e)

Data availability

All data associated with the research in this manuscript are findable, accessible, interoperable, and reusable.

Conflicts of interest

The authors have no conflict of interest.

Acknowledgements

The research fellowship provided by UGC (SA) and funding from the Ministry of Mines (Met4-14/19/2021), GOI are gratefully acknowledged.

Notes and references

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17. CCDC number of compound 9a: 1832647.†.
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Footnotes

† Electronic supplementary information (ESI) available: Details on synthesis, experimental procedure and additional spectra [NMR, ESI-MS]. CCDC 1832647 and 2312186. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4ob01004c

‡ These authors contributed equally.

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