Diastereoselective Cascade Cyclization of Diazoimides with Alkylidene Pyrazolones for Preparation of Pyrazole-Fused Oxa-Bridged Oxazocines

Under the catalysis of Rh2(OAc)4 (10 mol%) and binapbisphosphine ligand (±)-L3 (20 mol%) in DCE at 80 °C, the cascade cyclization of diazoimides with alkylidenepyrazolones underwent stereoselectively (dr > 20:1), affording pyrazole-fused oxa-bridged oxazocines in reasonable chemical yields. The chemical structure and relative configuration of title products were firmly identified by X-ray diffraction analysis.


Introduction
Oxazocines belong to a class of medicinally and biologically important chemical skeletons and have a wide range of biological activities such as anticancer, antibacterial, antidiabetic, and anti-Alzheimer properties [1,2] (Scheme 1 (1)).Due to the variety of the significant bioactive potentials with oxazocine scaffolds, organic and medicinal chemists have created a variety of synthetic methodologies for their efficient and concise constructions [3][4][5][6][7][8].Moreover, in this context, non-stereoselective and stereoselective cycloadditions have functioned as the crucial protocols for preparing a variety of structurally diverse and complex bridged and non-bridged oxazocines [9][10][11][12][13][14]. Importantly, elegant and powerful synthetic methodologies have appeared to prepare heterocycle-fused bridged oxazocines, but this area has witnessed slow development in recent years [15].So, designing and exploring new synthetic protocols is urgently needed to obtain structurally new and unique oxa-bridged oxazocines fused with heterocyclic motifs.
Molecules 2023, 28, x FOR PEER REVIEW 2 of 19 (20 mol%) in DCE at 80 °C, the newly designed cascade cyclization proceeded readily and diastereoselectively furnished pyrazole-fused oxa-bridged products 3 in reasonable chemical yields with excellent diastereoselectivities (>20:1 dr).Presumably, the formation of the aromatic pyrazole ring in the products substantially facilitates the cascade cyclization explored in our work.To the best of our knowledge, such a work has not been reported in the literature to date.
Table 1.Screening of metal-catalysts [a] .(20 mol%) in DCE at 80 °C, the newly designed cascade cyclization proceeded readily and diastereoselectively furnished pyrazole-fused oxa-bridged products 3 in reasonable chemical yields with excellent diastereoselectivities (>20:1 dr).Presumably, the formation of the aromatic pyrazole ring in the products substantially facilitates the cascade cyclization explored in our work.To the best of our knowledge, such a work has not been reported in the literature to date.Scheme 1. Representative bioactive oxazocines and the cascade cyclization in this work.

Entry
Moreover, with the use of Rh2(OAc)4 and (±)-L3 at 80 °C, we examined a variety of differently polar solvents for their effects on the cascade cyclization of diazoimide 1a with alkylidenepyrazolone 2a, as outlined in Table 3.Generally, in the screened solvents, the cascade cyclization formed product 3aa with excellent diastereoselectivity (>20:1 dr) (entries 1-8).However, the attempted solvents largely influenced the chemical yield of the cascade cyclization.Choosing DMF as the reaction solvent completely inhibited the occurrence of the cascade cyclization (entry 6).As for solvents HFIP and DCM, they afforded product 3aa in a trace amount after 10 h (entries 7 and 9).Using 1,4-dioxane and THF as the reaction solvents, cascade cyclization generated product 3aa in lower chemical yields (entries 2-3).Satisfyingly, we observed that in the aromatic solvents such as [a] Reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol) and [M] (10 mol%) in benzene (1.5 mL) at 80 °C. [b] Isolated yield. [c] Determined by 1 H NMR. [d] Reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol) and [M] (10 mol%) in benzene (1.5 mL) at 60 °C. [e] No reaction.

Entry
Moreover, with the use of Rh2(OAc)4 and (±)-L3 at 80 °C, we examined a variety of differently polar solvents for their effects on the cascade cyclization of diazoimide 1a with alkylidenepyrazolone 2a, as outlined in Table 3.Generally, in the screened solvents, the cascade cyclization formed product 3aa with excellent diastereoselectivity (>20:1 dr) (entries 1-8).However, the attempted solvents largely influenced the chemical yield of the cascade cyclization.Choosing DMF as the reaction solvent completely inhibited the occurrence of the cascade cyclization (entry 6).As for solvents HFIP and DCM, they afforded product 3aa in a trace amount after 10 h (entries 7 and 9).Using 1,4-dioxane and THF as the reaction solvents, cascade cyclization generated product 3aa in lower chemical yields (entries 2-3).Satisfyingly, we observed that in the aromatic solvents such as [a] Reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), Rh 2 (OAc) 4 (10 mol%), and ligand (20 mol%) in benzene (1.5 mL) at 80 • C. [b] Isolated yield. [c] Determined by 1 H NMR.
As for the cascade cyclization with alkylidenepyrazolone 2a, substrate 1 tolerated the variation in the R 1 group and the ring size of the lactam motif, and provided products 3ba-3ea in 70-82% chemical yields (entries 12-15).Basically, in this series, the 1 substrates possessing a bigger ring-sized lactam subunit commonly worked better than the 1 substrates incorporating a smaller ring-sized lactam subunit with respect to the chemical yield of the cascade cyclization (entries 13 vs. 14 vs. 15).As for substrate 1f containing a Isolated chemical yield. [c] Determined by 1 H NMR. [d] No reaction.
As for the cascade cyclization with alkylidenepyrazolone 2a, substrate 1 tolerated the variation in the R 1 group and the ring size of the lactam motif, and provided products 3ba-3ea in 70-82% chemical yields (entries [12][13][14][15].Basically, in this series, the 1 substrates possessing a bigger ring-sized lactam subunit commonly worked better than the 1 substrates incorporating a smaller ring-sized lactam subunit with respect to the chemical yield of the cascade cyclization (entries 13 vs. 14 vs. 15).As for substrate 1f containing a Nmethylacetamide motif, it performed poorly in the cascade cyclization with substrate 2a and produced product 3fa in a lower chemical yield (entry 16).Even worse, substrate 1g bearing a N-methylbenzamide subunit failed to conduct the cascade cyclization with substrate 2a (entry 17).Therefore, in this context, the 1 substrates containing a lactam motif generally have higher reactivities than the 1 substrates bearing a N-methylamide moiety (entries 12-15 vs. [16][17]. Moreover, with an aim of enriching the structural diversity and complexity of 3 products, we accomplished the crossed cascade cyclizations between substrates 1b-1e with a broad spectrum of 2 substrates, as presented in entries 18-41 (Table 4).Apparently, in this regard, all the conducted cascade cyclizations showed excellent diastereoselectivities (>20:1 dr).In the case of the chemical yields of the cascade cyclizations, they highly depended on the selected 1 and 2 substrates and ranged widely from 50% to 95%.Mostly, the crossed cascade cyclizations behaved well, and thus delivered 3 products in moderate to high chemical yields (entries 18-39 and 41).Only the cascade cyclization between 1e and 2n behaved poorly, and provided product 3ej in a quite low chemical yield (entry 40).Moreover, the oxindole-based enone 2q reacted well with diazoimide 1b, thus affording cycloadduct 3bl in excellent chemical yield and diastereoselectivity (entry 41).Meanwhile, we firmly identified the chemical structure and relative stereo-configuration of the desired product 3aa using single crystal X-ray analysis (CCDC 2260380) [45]; see details in SI) and assigned those of other title compounds by inference.In order to show the synthetic potentials of title 3 compounds, we prepared 3aa at gram scale and completed several chemical transformations of title compounds 3ba, 3aa, and 3cg, as described in Scheme 2. In the scale-up cascade cyclization, we isolated product 3aa at a chemical yield of 94% (Scheme 2(1)).Upon treatment with TMSCl in CH 2 Cl 2 at rt, compound 3ba easily converted into its exo/syn stereoisomer 4 (CCDC 2260381) [45]; see details in Supplementary Materials) at a chemical yield of 85% (Scheme 2(2)).Furthermore, the reduction reaction of 3aa with LiAlH 4 in anhydrous THF at 0 • C gave 5 at a chemical yield of 92%; and the addition reaction of 3aa with vinylmagnesium bromide in anhydrous THF at 0 • C produced 6 at a chemical yield of 75% (Scheme 2(3)).Lastly, in the presence of pyridine in EtOH at 60 • C, the condensation reaction between 3cg and H 2 NOMe•HCl furnished 7 at a chemical yield of 88% (Scheme 2(4)).
Molecules 2023, 28, x FOR PEER REVIEW 7 of 19 Lastly, in the presence of pyridine in EtOH at 60 °C, the condensation reaction between 3cg and H2NOMe•HCl furnished 7 at a chemical yield of 88% (Scheme 2(4)).
For the sake of clarifying the diastereoselective formation of product 3, we proposed the reaction mechanism for the cascade cyclization between diazoimide 1 and alkylidenepyrazolone 2, as illustrated in Scheme 3.Under the catalysis of Rh2(OAc)4 and (±)-L3, by liberating one molecule of N2, diazoimide 1 decomposes into Rh(II)-carbenoid Int-1.Then, Int-1 transforms into cyclic carbonyl ylide Int-2 through transition state TS-Scheme 2. Gram-scale synthesis of 3aa and chemical transformations of 3ba, 3aa, and 3cg.
For the sake of clarifying the diastereoselective formation of product 3, we proposed the reaction mechanism for the cascade cyclization between diazoimide 1 and alkylidenepyrazolone 2, as illustrated in Scheme 3.Under the catalysis of Rh 2 (OAc) 4 and (±)-L3, by liberating one molecule of N 2 , diazoimide 1 decomposes into Rh(II)-carbenoid Int-1.Then, Int-1 transforms into cyclic carbonyl ylide Int-2 through transition state TS-1.Concerning Int-2, which was formed in situ, it can conduct the cascade cyclization with alkylidenepyrazolone 2 by adopting transition states TS-2 or TS-3.In TS-3, there exists strong steric repulsion between R 1 and R 2 motifs; in contrast, TS-2 fully avoids this kind of unfavorable interaction.So, TS-2 is thermodynamically more stable than TS-3 and mainly accounts for the formation of single endo/anti-3.

Materials and Methods
Proton ( 1 H), carbon ( 13 C), and fluorine ( 19 F) NMR spectra were recorded on a Bruker Avance HD III spectrometer (400 MHz for 1 H NMR, 100 MHz for 13 C NMR, and 376 MHz for 19 F NMR) and calibrated using tetramethylsilane (TMS) as internal reference.High resolution mass spectra (HRMS) were obtained on an Agilent Technologies LC/MSD TOF spectrometer under electrospray ionization (ESI) conditions.The melting point of compounds was determined using a melting point instrument.Flash column chromatography was performed on silica gel (0.035-0.070 mm) using compressed air.Xray single crystals were obtained on a Rigaku 002 Saturn 944 spectrometer.Thin layer chromatography (TLC) was carried out on 0.25 mm SDS silica gel coated glass plates (60F254).Eluted plates were visualized using a 254 nm UV lamp.Unless otherwise indicated, all reagents were commercially available and used without further purification.All solvents were distilled from the appropriate drying agents immediately before use.Diazoimides 1a-1g were synthesized according to the reported procedures [10,46,47].Alkylidenepyrazolones 2a-2q were prepared according to literature procedures [48][49][50].

Materials and Methods
Proton ( 1 H), carbon ( 13 C), and fluorine ( 19 F) NMR spectra were recorded on a Bruker Avance HD III spectrometer (400 MHz for 1 H NMR, 100 MHz for 13 C NMR, and 376 MHz for 19 F NMR) and calibrated using tetramethylsilane (TMS) as internal reference.High resolution mass spectra (HRMS) were obtained on an Agilent Technologies LC/MSD TOF spectrometer under electrospray ionization (ESI) conditions.The melting point of compounds was determined using a melting point instrument.Flash column chromatography was performed on silica gel (0.035-0.070 mm) using compressed air.X-ray single crystals were obtained on a Rigaku 002 Saturn 944 spectrometer.Thin layer chromatography (TLC) was carried out on 0.25 mm SDS silica gel coated glass plates (60F254).Eluted plates were visualized using a 254 nm UV lamp.Unless otherwise indicated, all reagents were commercially available and used without further purification.All solvents were distilled from the appropriate drying agents immediately before use.Diazoimides 1a-1g were synthesized according to the reported procedures [10,46,47].Alkylidenepyrazolones 2a-2q were prepared according to literature procedures [48][49][50].

Materials and Methods
Proton ( 1 H), carbon ( 13 C), and fluorine ( 19 F) NMR spectra were recorded on a Bruker Avance HD III spectrometer (400 MHz for 1 H NMR, 100 MHz for 13 C NMR, and 376 MHz for 19 F NMR) and calibrated using tetramethylsilane (TMS) as internal reference.High resolution mass spectra (HRMS) were obtained on an Agilent Technologies LC/MSD TOF spectrometer under electrospray ionization (ESI) conditions.The melting point of compounds was determined using a melting point instrument.Flash column chromatography was performed on silica gel (0.035-0.070 mm) using compressed air.Xray single crystals were obtained on a Rigaku 002 Saturn 944 spectrometer.Thin layer chromatography (TLC) was carried out on 0.25 mm SDS silica gel coated glass plates (60F254).Eluted plates were visualized using a 254 nm UV lamp.Unless otherwise indicated, all reagents were commercially available and used without further purification.All solvents were distilled from the appropriate drying agents immediately before use.Diazoimides 1a-1g were synthesized according to the reported procedures [10,46,47].Alkylidenepyrazolones 2a-2q were prepared according to literature procedures [48][49][50].

Gram-Scale Synthesis of Compound 3aa
Molecules 2023, 28, x FOR PEER REVIEW 9 of 19

Chemical Transformations of 3ba, 3aa, and 3cg
To a well-stirred solution of 3ba (1.0 equiv, 0.1 mmol, 38.7 mg) in CH2Cl2 (1.0 mL), TMSCl (1.0 equiv, 0.1 mmol, 10.8 mg) was added.Then, the reaction mixture was stirred at room temperature for 12 h.After the reaction was finished as indicated by the TLC plate, the reaction mixture was concentrated under reduced pressure.The resulting reaction residue was purified using flash column chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford product 4 as a white solid (32.8To a well-stirred solution of 3aa (1.0 equiv, 0.1 mmol, 42.9 mg) in dry THF (1.0 mL), LiAlH4 (2.0 equiv, 0.2 mmol, 7.6 mg) was added.Then, the reaction mixture was stirred at 0 °C for 1 h.After the reaction was finished as indicated by the TLC plate, the reaction mixture was concentrated under reduced pressure.The resulting reaction residue was purified using flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to afford product 5 as a white solid (39.7 mg, 92% yield).M.P. = 215.7216.1 °C; 1  A mixture of diazoimide 1a (1.5 equiv, 6.0 mmol, 1.168 g), alkylidenepyrazolone 2a (1.0 equiv, 4.0 mmol, 1.048 g), Rh 2 (OAc) 4 (10.0 mol%, 0.176 g), and (±)-L3 (20.0 mol%, 0.497 g) in DCE (15 mL) was stirred at 80 • C.After the reaction was completed as indicated by the TLC plate, the solvent was concentrated under reduced pressure and the resulting crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford product 3aa as a white solid (1.614 g, 94% yield).