Desymmetrization of Prochiral N-Pyrazolyl Maleimides via Organocatalyzed Asymmetric Michael Addition with Pyrazolones: Construction of Tri-N-Heterocyclic Scaffolds Bearing Both Central and Axial Chirality

The desymmetrization of N-pyrazolyl maleimides was realized through an asymmetric Michael addition by using pyrazolones under mild conditions, leading to the formation of a tri-N-heterocyclic pyrazole–succinimide–pyrazolone assembly in high yields with excellent enantioselectivities (up to 99% yield, up to 99% ee). The use of a quinine-derived thiourea catalyst was essential for achieving stereocontrol of the vicinal quaternary–tertiary stereocenters together with the C–N chiral axis. Salient features of this protocol included a broad substrate scope, atom economy, mild conditions and simple operation. Moreover, a gram-scale experiment and derivatization of the product further illustrated the practicability and potential application value of this methodology.

Pyrazoles and pyrazolones are among the important five-membered N-heterocycles that can be found in numerous bioactive molecules and drugs, possessing unique biological and pharmacological activities (Scheme 2a) [27][28][29]. For example, edaravone (1) is a neuroprotective agent [30], and aminopyrine (2) and antipyrine (3) are used to treat migraine headaches [31]. In addition, some pyrazole-lactim derivatives are also considered as important structural motifs of bioactive molecules and have been widely explored in many applications, such as a nervous system drug molecule (4) [32], antidiabetic agent (5) [33] and immunologically active compound (6) [34]. Considering the significance of axially chiral scaffolds and the distinctive biological activities of pyrazolone and pyrazole skeletons mentioned above, we envisaged the development Since the first report on the C-N axially chiral framework of N-phenylpyrrole by Adams in 1931 [35], the construction of novel axially chiral N-aryl heterocyclic molecules was reported successively, giving a series of N-aryl lactam, pyrrole, indole or imide heterocyclic skeletons [36]. Overall, among the reported synthetic strategies, the desymmetrization reaction, starting from simple and easily available prochiral substrates, was regarded as a valuable and efficient approach, which further constructed multiple chiral centers at the reaction site and the prochiral center at the same time. In this regard, Bencivenni's group reported the first construction of enantiomerically enriched atropisomeric succinimides via an organocatalytic asymmetric vinylogous Michael addition reaction of N-arylmaleimides in 2014 (Scheme 2b) [37]. Subsequently, Bencivenni and co-workers disclosed a novel desymmetrization strategy to construct axially chiral succinimides bearing a C-N axis and contiguous stereocenters by a formal Diels-Alder desymmetrization reaction (Scheme 2b) [38]. In 2021, Biju's group reported an atroposelective synthesis of C-N axially chiral N-aryl succinimides based on the Nheterocyclic carbene-catalyzed Stetter-aldol-oxidation cascade process (Scheme 2b) [39]. More recently, following a related strategy, Liao's group successfully achieved the desymmetrization reaction of prochiral N-aryl maleimide by silver-catalyzed asymmetric [3 + 2] cycloaddition (Scheme 2b) [40]. Inspired by the above methods and based on our continuous interest in pyrazole and pyrazolone skeletons, we herein report an enantioselective desymmetrization of a new prochiral N-pyrazolyl maleimide through an asymmetric Michael addition reaction with pyrazolones to construct a tri-N-heterocyclic pyrazole-succinimide-pyrazolone assembly bearing vicinal quaternary-tertiary stereocenters together with a C-N chiral axis (Scheme 2c). Since the first report on the C-N axially chiral framework of N-phenylpyrrole by Adams in 1931 [35], the construction of novel axially chiral N-aryl heterocyclic molecules was reported successively, giving a series of N-aryl lactam, pyrrole, indole or imide heterocyclic skeletons [36]. Overall, among the reported synthetic strategies, the desymmetrization reaction, starting from simple and easily available prochiral substrates, was regarded as a valuable and efficient approach, which further constructed multiple chiral centers at the reaction site and the prochiral center at the same time. In this regard, Bencivenni's group reported the first construction of enantiomerically enriched atropisomeric succinimides via an organocatalytic asymmetric vinylogous Michael addition reaction of N-arylmaleimides in 2014 (Scheme 2b) [37]. Subsequently, Bencivenni and co-workers disclosed a novel desymmetrization strategy to construct axially chiral succinimides bearing a C-N axis and contiguous stereocenters by a formal Diels-Alder desymmetrization reaction (Scheme 2b) [38]. In 2021, Biju's group reported an atroposelective synthesis of C-N axially chiral N-aryl succinimides based on the N-heterocyclic carbene-catalyzed Stetter-aldol-oxidation cascade process (Scheme 2b) [39]. More recently, following a related strategy, Liao's group successfully achieved the desymmetrization reaction of prochiral N-aryl maleimide by silver-catalyzed asymmetric [3 + 2] cycloaddition (Scheme 2b) [40]. Inspired by the above methods and based on our continuous interest in pyrazole and pyrazolone skeletons, we herein report an enantioselective desymmetrization of a new prochiral N-pyrazolyl maleimide through an asymmetric Michael addition reaction with pyrazolones to construct a tri-N-heterocyclic pyrazole-succinimide-pyrazolone assembly bearing vicinal quaternary-tertiary stereocenters together with a C-N chiral axis (Scheme 2c).
With the optimized reaction conditions in hand, we next explored the scope of pyrazolone 1 and the results were shown in Scheme 3. The results showed that these reactants were well tolerated, and most reactions could be accomplished within 4 h to afford the axially chiral product 3 in good yield (up to 99% yield) with excellent enantioselectivity (up to 99% ee). First, pyrazolone substrates bearing different aryl groups (R 1 ) at the C-3 position of the pyrazolone unit were examined. When a methyl group was introduced into the ortho, meta and para positions of the phenyl substituents at the pyrazolone unit, the product 3ba-3da could be obtained in a 99% yield with 1:1 dr and high enantioselectivities (98-99% ee). However, when R 1 was a naphthalene substituent, the yield of the target compound 3ea was only 79% due to the influence of steric hindrance. In addition, when the substituted phenyl group was replaced by a thiophene substituent, product 3fa was formed in 99% yield with 1:1 dr and 99% ee. To our delight, methyl proved to be a suitable substituent leading to the target product 3ga in a 97% yield with 1:1 dr and excellent enantioselectivity (99% ee). To further expand the reaction scope of the pyrazolone unit, additional substituent groups (R 2 ) were also explored. A series of substituents on the ortho, meta and para positions of the benzene ring were well tolerated, such as those bearing halides (3ha, 3ia), NO 2 (3ja), methyl (3ka, 3la) and methoxyl (3ma) in high yields (95-99%) with 1:1 dr and excellent enantioselectivities (86-99% ee). When the benzene ring was replaced by 3,5bis(trifluoromethyl)phenyl, the yield and enantioselectivity were maintained, leading to the formation of product 3na in a 97% yield with 1:1 dr and 95% ee. In addition, the naphthalene-containing substrate 1o was also tested to afford the corresponding 3oa in 94% ee, but the yield was reduced to 74%, probably because of the steric hindrance of the bulky substituent. Table 1. Optimization of reaction conditions. 3aa to 91% ee (entry 11). In order to further enhance the enantioselectivity of the the solvent (entries 12-16) effect was then examined and the results revealed tha was optimal with regard to both the yield and enantioselectivity, and 99% yield ee were observed (entry 12). Finally, the concentration and temperature were inve (entries [17][18][19], and the best condition was confirmed with 10 mol% of C10 in toluene at 25 °C, affording the product 3aa in a 99% yield with 1:1 dr and 99% e 17). Table 1. Optimization of reaction conditions. but no enantioselectivity was obtained in this reaction (entry 6). Moreover, with the quinine-derived N-Boc-protected catalyst C6, no improvement was observed in terms of the enantioselectivity and the yield of 3aa dropped to 85% (entry 7). When using sulfonamide C7 and quaternary ammonium salt C8, the target product 3aa was generated only in moderate yields with poor enantioselectivities (entries [8][9]. Subsequently, we used quinine-derived thiourea catalysts C9 and C10 to perform this reaction (entries [10][11], and to our surprise, the catalyst C10 could increase the enantioselectivity of product 3aa to 91% ee (entry 11). In order to further enhance the enantioselectivity of the reaction, the solvent (entries 12-16) effect was then examined and the results revealed that toluene was optimal with regard to both the yield and enantioselectivity, and 99% yield and 94% ee were observed (entry 12). Finally, the concentration and temperature were investigated (entries [17][18][19], and the best condition was confirmed with 10 mol% of C10 in 2 mL of toluene at 25 °C, affording the product 3aa in a 99% yield with 1:1 dr and 99% ee (entry 17).

Gram-Scale Reaction and Transformation of Products
To demonstrate the scalability of this protocol, we conducted a gram-scale reaction of pyrazolone 1i with pyrazolyl-maleimide 2a under the standard reaction conditions, and the product 3ia was successfully obtained in a 91% yield with 1:1 dr and 96% ee (Scheme 5a). Subsequently, the selective bromination of compound 3ia in the presence of NBS proceeded smoothly, producing the product 4 in a 58% yield, >20:1 dr and 96% ee. The excellent diastereoselective results revealed that the bromination at the C-4 position of the pyrazole ring played an important role in controlling the stereoselectivity of the reaction. The N-1 and C-4 positions of the pyrazole ring were substituted with tert-butyl and bromine, respectively, and their large steric hindrance effect successfully achieved good stereoselective control of the C-N axis (Scheme 5b). In order to further prove the existence of the C-N axis in the target products, a Michael reaction of 4-nonsubstituted pyrazolone 5 and pyrazolyl-maleimide 2a was performed under similar reaction conditions, followed by esterification using acetic anhydride to produce the compound 6 in a 60% yield with 6:1 dr. This diastereomeric ratio indicated that the product 6 contained two chiral elements, namely center chirality and axial chirality (Scheme 5c).

Gram-Scale Reaction and Transformation of Products
To demonstrate the scalability of this protocol, we conducted a gram-scale reaction of pyrazolone 1i with pyrazolyl-maleimide 2a under the standard reaction conditions, and the product 3ia was successfully obtained in a 91% yield with 1:1 dr and 96% ee (Scheme 5a). Subsequently, the selective bromination of compound 3ia in the presence of NBS proceeded smoothly, producing the product 4 in a 58% yield, >20:1 dr and 96% ee. The excellent diastereoselective results revealed that the bromination at the C-4 position of the pyrazole ring played an important role in controlling the stereoselectivity of the reaction. The N-1 and C-4 positions of the pyrazole ring were substituted with tert-butyl and bromine, respectively, and their large steric hindrance effect successfully achieved good stereoselective control of the C-N axis (Scheme 5b). In order to further prove the existence of the C-N axis in the target products, a Michael reaction of 4-nonsubstituted pyrazolone 5 and pyrazolyl-maleimide 2a was performed under similar reaction conditions, followed by esterification using acetic anhydride to produce the compound 6 in a 60% yield with 6:1 dr. This diastereomeric ratio indicated that the product 6 contained two chiral elements, namely center chirality and axial chirality (Scheme 5c).

Plausible Transition State for the Enantioselective Desymmetrization
On the basis of the reaction results and previous similar reports [37,38,41,42], a plausible reaction transition state for the desymmetrization was proposed in Scheme 6. The transition state was made up of a ternary complex in which catalyst C10 promoted the formation of a reactive enolate and at the same time anchored the maleimide by means of hydrogen bonds with the thiourea functional group. In addition, there may have existed a π-π interaction between the phenyl of pyrazolone and the naphthalene ring of catalyst C10 that played an important role in the control of the enantioselectivity of the target product. Subsequently, succinimides with two adjacent stereocenters were gener-ated via an asymmetric Michael reaction, which further obtained the C-N axially chiral pyrazolyl-succinimide 3.
Molecules 2023, 28, x FOR PEER REVIEW 8 of 22 Scheme 5. Gram-scale reaction and transformation of products.

Plausible Transition State for the Enantioselective Desymmetrization
On the basis of the reaction results and previous similar reports [37,38,41,42], a plausible reaction transition state for the desymmetrization was proposed in Scheme 6. The transition state was made up of a ternary complex in which catalyst C10 promoted the formation of a reactive enolate and at the same time anchored the maleimide by means of hydrogen bonds with the thiourea functional group. In addition, there may have existed a π-π interaction between the phenyl of pyrazolone and the naphthalene ring of catalyst C10 that played an important role in the control of the enantioselectivity of the target product. Subsequently, succinimides with two adjacent stereocenters were generated via an asymmetric Michael reaction, which further obtained the C-N axially chiral pyrazolylsuccinimide 3.

Scheme 5. Gram-scale reaction and transformation of products.
Molecules 2023, 28, x FOR PEER REVIEW 9 of 22 Scheme 6. Plausible transition state for the enantioselective desymmetrization.

General Information
Unless otherwise noted, the materials were purchased from commercial suppliers and used without further purification. Column chromatography was performed on silica

General Information
Unless otherwise noted, the materials were purchased from commercial suppliers and used without further purification. Column chromatography was performed on silica gel (200~300 mesh). Enantiomeric excesses (ee) were determined by HPLC (Agilent, Palo Alto, CA, USA) using the corresponding commercial chiral columns as stated at 25 • C with a UV detector at 254 nm. Optical rotations (JiaHang Instruments, Shanghai, China) were reported as follows: [α] T D (c g/100 mL, solvent). All 1 H NMR and 19 F NMR spectra were recorded on a Bruker Avance II 400 MHz (Bruker, Karlsruhe, Germany) and Bruker Avance III 600 MHz (Bruker, Karlsruhe, Germany), respectively; (Supplementary Materials) 13 C NMR spectra were recorded on a Bruker Avance II 101 MHz or Bruker Avance III 151 MHz with chemical shifts reported as ppm (in CDCl 3 , TMS as an internal standard). Data for 1 H NMR were recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad singlet, dd = double doublet, coupling constants in Hz and integration). HRMS (ESI) was obtained with an HRMS/MS instrument (LTQ Orbitrap XL TM, Agilent, Palo Alto, CA, USA). The absolute configuration of 4 was assigned by the X-ray analysis.

Procedure for the Synthesis of Compounds 2
The compound 5-Aminopyrazole was prepared according to the literature [43]. The maleic anhydride (7.5 mmol) and 5-aminopyrazole (5 mmol) were dissolved in 10 mL CHCl 3 , stirred for 10 h and the solid (maleimide acid) precipitated from the reaction mixture was filtered. Maleimide acid was dissolved in 20 mL acetic anhydride and 200 mg sodium acetate was added. The mixture was heated at 85 • C and stirred for 4 h. The reaction was cooled and quenched with water, then the mixture was filtered, quenched with water and extracted with ethyl acetate. The organic phase was separated, washed with water and dried over Na 2 SO 4 . The product was purified by silica gel column chromatography with a mixture of petroleum ether and ethyl acetate (10:1) as eluent. The target compound 2 (0.96 g, 65 %) was obtained as a solid.