Construction of N-Aryl-Substituted Pyrrolidines by Successive Reductive Amination of Diketones via Transfer Hydrogenation

N-aryl-substituted pyrrolidines are important moieties widely found in bioactive substances and drugs. Herein, we present a practical reductive amination of diketones with anilines for the synthesis of N-aryl-substituted pyrrolidines in good to excellent yields. In this process, the N-aryl-substituted pyrrolidines were furnished via successive reductive amination of diketones via iridium-catalyzed transfer hydrogenation. The scale-up performance, water as a solvent, simple operation, as well as derivation of drug molecules showcased the potential application in organic synthesis.

Despite the great progress achieved in the construction of N-aryl-substituted pyrrolidines, challenges still exist in terms of selectivity, substrate versatility, reaction conditions, as well as catalytic efficiency [45,46].Among the general strategies for pyrrolidine synthesis, reductive amination is undoubtedly the most efficient approach.In this process, the reaction of carbonyl compounds with amines took place first to afford C=N intermediates, which was then followed by the reduction process to form C-N bonds, in which water is the only by-product.Nevertheless, an excess of expensive hydrides or silanes was generally required as a reductant in these traditional processes [16][17][18][19][20][21][22][23].Therefore, a cheap and efficient catalytic system is still in demand for pyrrolidine synthesis.Metal-catalyzed transfer hydrogenation employed as a supplement to conventional hydrogenation drew much attention and was extensively utilized in organic synthesis [47].In this context, hydrogen donors such as formic acid were widely utilized in differential transfer hydrogenation reactions owing to their potential hydrogen storage, low toxicity, as well as ease of handling [48].We have great interest in transfer hydrogenation and conducted a series of relative studies using iridium complexes as catalysts [49], by which reduction in unsaturated compounds [50,51], silane oxidation [52], N-allylic alkylation [53], reductive amination [54], reductive amination [55], as well as reductive etherification [56] were reported.Recently, we established a one-pot procedure for synthesizing amines via reduction-reductive amination (Scheme 2a) [57].Based on previous work, we envisioned that this approach could also be employed for the construction of N-aryl-substituted pyrrolidines via successive reductive amination.Herein, we describe an iridium-catalyzed successive reductive amination of diketones with anilines, offering N-aryl-substituted pyrrolidines in good to excellent yields under mild conditions (Scheme 2b).This protocol provides a new route for azacycle synthesis.Metal-catalyzed transfer hydrogenation employed as a supplement to conventional hydrogenation drew much attention and was extensively utilized in organic synthesis [47].In this context, hydrogen donors such as formic acid were widely utilized in differential transfer hydrogenation reactions owing to their potential hydrogen storage, low toxicity, as well as ease of handling [48].We have great interest in transfer hydrogenation and conducted a series of relative studies using iridium complexes as catalysts [49], by which reduction in unsaturated compounds [50,51], silane oxidation [52], N-allylic alkylation [53], reductive amination [54], reductive amination [55], as well as reductive etherification [56] were reported.Recently, we established a one-pot procedure for synthesizing amines via reduction-reductive amination (Scheme 2a) [57].Based on previous work, we envisioned that this approach could also be employed for the construction of N-aryl-substituted pyrrolidines via successive reductive amination.Herein, we describe an iridium-catalyzed successive reductive amination of diketones with anilines, offering N-aryl-substituted pyrrolidines in good to excellent yields under mild conditions (Scheme 2b).This protocol provides a new route for azacycle synthesis.Metal-catalyzed transfer hydrogenation employed as a supplement to conventional hydrogenation drew much attention and was extensively utilized in organic synthesis [47].In this context, hydrogen donors such as formic acid were widely utilized in differential transfer hydrogenation reactions owing to their potential hydrogen storage, low toxicity, as well as ease of handling [48].We have great interest in transfer hydrogenation and conducted a series of relative studies using iridium complexes as catalysts [49], by which reduction in unsaturated compounds [50,51], silane oxidation [52], N-allylic alkylation [53], reductive amination [54], reductive amination [55], as well as reductive etherification [56] were reported.Recently, we established a one-pot procedure for synthesizing amines via reduction-reductive amination (Scheme 2a) [57].Based on previous work, we envisioned that this approach could also be employed for the construction of N-aryl-substituted pyrrolidines via successive reductive amination.Herein, we describe an iridium-catalyzed successive reductive amination of diketones with anilines, offering N-aryl-substituted pyrrolidines in good to excellent yields under mild conditions (Scheme 2b).This protocol provides a new route for azacycle synthesis.

Results and Discussion
The development of this iridium-catalyzed reductive amination reaction began with the model reaction of 2,5-hexanedione (1a) with aniline (2a) (Table 1).Catalyst screening indicated similar yields of mixed products of N-phenyl-substituted pyrrolidine 3a1 and N-phenyl-substituted pyrrole 3a1 ′ were formed simultaneously (Table 1, entries 1-6).To afford the appropriate conditions for N-phenyl-substituted pyrrolidine synthesis, further reaction conditions were screened.Solvent optimization (Table 1, entries 7-13) showed that water was beneficial to the formation of the desired pyrrolidine 3a1 in 80% yield, in which the pyrrole product 3a1 ′ was inhibited (Table 1, entry 12).Notably, the increasing loading of HCO 2 H is helpful for the transformation of the desired pyrrolidine product 3a1 (Table 1, entries 14-17).For instance, a 92% isolated yield of N-phenyl-substituted pyrrolidine 3a1 was generated in 71:29 dr by increasing the dosage of HCO 2 H to 30.0 equivalent (Table 1, entry 17).Similar excellent yields of pyrrolidine 3a1 were afforded by increasing the reaction temperature to 100 • C, even shortening the reaction time (Table 1, entries 18 and 19).In comparison, only 60% yield of 3a1 in 50:50 dr was obtained when the reaction was performed at room temperature (Table 1, entry 20).Control experiments showed both the catalyst and formic acid were essential for this transformation (Table 1, entries 21 and 22).
Table 1.Condition optimization of the iridium-catalyzed successive reductive amination for the synthesis of N-phenyl-substituted pyrrolidine (3a1) a .
shown in Scheme 4, similar moderate yields but excellent stereoselectivities (>99:1 dr) of N-aryl-substituted pyrrolidines (3b1, 3b2~3b4) were afforded via reductive amination of 1-phenylhexane-1,4-dione (1b) with para-substituted aromatic amines, in which the configuration of 3b4 was determined by X-ray crystallography [58].However, decreased stereoselectivities of the desired product (3b5, 3b6) were observed using ortho-and para-substituted aromatic amines as nucleophiles and 1-phenylhexane-1,4-dione (1b) as substrate.Obviously, employing more steric hinderance of octane-3,6-dione (1c) as substrate resulted in similar moderate yields and stereoselectivities (3c1 and 3c2).Surprisingly, the formation of pyrrole as a major product (3c3′) was observed by using 4-iodoaniline (2y) as a nucleophile, delivering a reductive amination product of 3c3 in lower yield.To further illustrate the utility of this iridium-catalyzed reductive amination, the model reaction was subjected to a gram-scale performance under standard conditions (Scheme 5).As expected, 10.0 mmol of the compound 1a was successfully converted into 1.61 g of the corresponding product 3a1 in a 92% yield.To shed light on the process of this Ir-catalyzed reductive amination, control experiments were conducted to explore more details of this transformation.Firstly, to probe whether the pyrrole is involved as an intermediate in this reductive amination process, a control experiment using 3a1′ as substrate was performed under standard conditions R = H, 3b1 (63%,>99:1) R = O-iPr, 3b2 (69%,>99:1) R = t-Bu, 3b3, ( 63%,>99:1) R = Bn, 3b4, (69%,>99 To further illustrate the utility of this iridium-catalyzed reductive amination, the model reaction was subjected to a gram-scale performance under standard conditions (Scheme 5).As expected, 10.0 mmol of the compound 1a was successfully converted into 1.61 g of the corresponding product 3a1 in a 92% yield.
shown in Scheme 4, similar moderate yields but excellent stereoselectivities (>99:1 N-aryl-substituted pyrrolidines (3b1, 3b2~3b4) were afforded via reductive aminati 1-phenylhexane-1,4-dione (1b) with para-substituted aromatic amines, in which configuration of 3b4 was determined by X-ray crystallography [58].However, decre stereoselectivities of the desired product (3b5, 3b6) were observed using ortho-an ra-substituted aromatic amines as nucleophiles and 1-phenylhexane-1,4-dione (1 substrate.Obviously, employing more steric hinderance of octane-3,6-dione (1c) as strate resulted in similar moderate yields and stereoselectivities (3c1 and 3c2).Su ingly, the formation of pyrrole as a major product (3c3′) was observed by 4-iodoaniline (2y) as a nucleophile, delivering a reductive amination product of 3 lower yield.To further illustrate the utility of this iridium-catalyzed reductive amination model reaction was subjected to a gram-scale performance under standard cond (Scheme 5).As expected, 10.0 mmol of the compound 1a was successfully converted 1.61 g of the corresponding product 3a1 in a 92% yield.To shed light on the process of this Ir-catalyzed reductive amination, contro periments were conducted to explore more details of this transformation.Firstly, to p whether the pyrrole is involved as an intermediate in this reductive amination proc control experiment using 3a1′ as substrate was performed under standard cond To shed light on the process of this Ir-catalyzed reductive amination, control experiments were conducted to explore more details of this transformation.Firstly, to probe whether the pyrrole is involved as an intermediate in this reductive amination process, a control experiment using 3a1 ′ as substrate was performed under standard conditions (Scheme 6a).However, no expected pyrrolidine product 3a1 was observed, strongly suggesting that the pyrrolidine product was not produced via the transfer hydrogenation of pyrrolidine.

Experimental Section
All the reactions were carried out in oven-dried Schlenk tubes.All the reagents and anhydrous solvents were purchased from commercial sources and used without further purification.Silica gel (100~200 mesh) bought from commercial sources was used for column chromatography.Purified hexane or a mixture of petroleum ether and ethyl acetate was used as a gradient eluent for column chromatography. 1 H and 13 C NMR spectra were recorded using a Bruker DRX-400 spectrometer (Bruker, Ettlingen, Germany) (400 MHz for 1H; 101 MHz for 13 C).The chemical shifts are referenced to the resonances of the residual protons in the deuterated solvents.The abbreviations [s = singlet, d = doublet, t = triplet, m = multiplet, br = broad coupling constants are given in Hertz (Hz)] were used to designate the chemical shift multiplicities.All NMR quantitative analyses were performed with dimethyl terephthalate as the internal standard.High-resolution mass spectra (HRMS) were recorded by an LCMS-IT-TOF mass spectrometer.Melting points were obtained on the WRR melting point apparatus without correction.Fourier transform infrared spectra (FT-IR) were recorded on a Thermofisher Nicolet iS50 (Thermo, Waltham, MA, USA) spectrometer.

General Procedure for Construction of N-Aryl-Substituted Pyrrolidines
To a 25.0 mL dried Schlenk tube, add catalyst TC-2 [60] (1.0 mol%), 1 (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.1 equiv.),solvent (2.0 mL), and hydrogen donor HCO 2 H (30.0 equiv.), which was stirred under air at 80 • C for 12 h.After the completion of the reaction, the mixture was dissolved in ethyl acetate and washed with saturated salt water 2~3 times, and then the organic fraction was dried over anhydrous Na 2 SO 4 .The residue was separated and refined by chromatography on silica gel with hexane or a mixture of petroleum ether and ethyl acetate as the eluent to afford product 3.

Conclusions
Overall, we have developed a practical successive reductive amination of diketones with anilines for the construction of N-aryl-substituted pyrrolidines in good to excellent yields and stereoselectivities.This method features scale-up performance, water as a solvent, simple operation, as well as the derivation of drug molecules.Mechanistic studies indicated competitive pathways of Paal-knorr condensation reaction and Ir-catalyzed transfer hydrogenation to produce pyrrole and pyrrolidine products, respectively.Further efforts into the mechanistic details as well as explorations of the medical applications of the N-aryl-substituted pyrrolidine products are currently underway in our laboratory.

Author Contributions:
Conceptualization, R.L.; Methodology, J.T. and L.L.; Resources, R.L.; Data curation, L.O.; Writing-original draft, J.L.; Writing-review & editing, R.L.All authors have read and agreed to the published version of the manuscript.Funding: This work was supported by the National Natural Science Foundation of China (22161004), the Fundamental Research Funds for Gannan Medical University (QD202019, QD202106, TD2021YX05) and Shaoguan University (408/9900064703) for financial support.

Table 1 .
Condition optimization of the iridium-catalyzed successive reductive amination for th synthesis of N-phenyl-substituted pyrrolidine (3a1) a .