Stereoselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations to Access Functionalized 1,4-Benzodiazepin-3-ones

The 1,4-benzodiazepine structural framework is a fascinating element commonly found in biologically active and pharmaceutically relevant compounds. A highly efficient method for synthesizing 1,4-benzodiazepin-3-ones is described, involving a [4+3]-cycloaddition reaction between 2-amino-β-nitrostyrenes and α-bromohydroxamate, with Cs2CO3 used as a base. This process yielded the desired 1,4-benzodiazepines in good yields. Furthermore, an organocatalytic asymmetric [4+3]-cycloaddition was successfully accomplished using a bifunctional squaramide-based catalyst. This approach enabled the enantioselective synthesis of chiral 1,4-benzodiazepines with commendable yields and moderate enantioselectivities, reaching up to 80% yield and 72% ee.


Introduction
N,N-Heterocycles are prevalent in various natural products and pharmaceuticals, making them crucial structural elements in medicinal chemistry [1,2].Among these, 1,4benzodiazepinone, which is a seven-membered lactam, presents a structural framework frequently observed in numerous natural substances.Derivatives of this compound can exhibit a wide range of biological activities and valuable pharmaceutical characteristics, indicating their promise as potential candidates for drug discovery (Figure 1) [3][4][5][6][7][8][9].Currently, this seven-membered structural framework is prevalent in numerous drug molecules with distinct bioactivities.For instance, Diazepam, initially introduced to the market as Valium, belongs to the benzodiazepine family and serves as an anxiolytic medication.It is frequently prescribed to address various conditions, such as anxiety, seizures, muscle spasms, and insomnia [10].Additionally, Lotrafiban belongs to the latest generation of platelet GPIIb/IIIa blockers, representing a significant advancement in interventional cardiology and the treatment of acute ischemic syndrome, aimed at preventing vascular occlusion [11,12].
Indeed, the effective synthesis of a wide range of functionally diverse 1,4-benzodiazepinone derivatives has garnered considerable research attention [4,[13][14][15][16][17].However, the synthesis of a seven-membered ring 1,4-benzodiazepinone presents difficulties due to unfavorable enthalpic and entropic factors that hinder the ring closure process [18].Consequently, achieving efficient access to 1,4-benzodiazepinone represents a significant and demanding task in the field of organic synthesis.While there have been numerous reported synthetic routes for 1,4-benzodiazepinones over the past decade, it is noteworthy that there are very limited instances of one-pot and asymmetric synthesis methods available [19].

Non-Enantioselective [4+3]-Cycloaddition of 2-Amino-β-Nitrostyrenes with Azaoxyallyl Cations
To begin our study, our primary objective was to determine the feasibility of the [4+3]-cycloaddition involving 2-amino-β-nitrostyrenes [24] and α-bromohydroxamates.In our initial experiment, we conducted a reaction involving 2-amino-β-nitrostyrene 1a and αbromohydroxamate 2a, employing Cs2CO3 as a base and HFIP as an additive.This reaction was carried out in toluene at room temperature, resulting in the desired 1,4benzodiazepine-3-ones 3a in an 18% yield (Table 1, entry 1).Despite the initial low yield, these promising results served as a source of motivation to drive further investigations.We embarked on a systematic approach to establish and optimize the reaction conditions for the [4+3]-cycloaddition involving 2-amino-β-nitrostyrene 1a and αbromohydroxamate 2a.In our quest to identify the optimal reaction conditions for the [4+3]-cycloaddition reaction, we observed a notable improvement when we switched the solvent to CH2Cl2, resulting in an increased yield of 55% (Table 1, entry 2).Subsequently, we introduced HFIP as a co-solvent.It is worth noting that many cycloadditions involving azaoxyallyl cations have demonstrated enhanced performance in HFIP solutions.This can be attributed to HFIP's distinctive properties, such as its strong hydrogen bond donation and high ionizing power, which effectively stabilize azaoxyallyl cations [25,26].The incorporation of a CH2Cl2/HFIP co-solvent system significantly improved the yield of 1,4benzodiazepine-3-one 3a, elevating it to 85%.Moreover, adjusting the solvent concentration to 0.2 M led to a further increase in yield, reaching an impressive 91%.(Table 1, entries 3 and 4).Further efforts to optimize the reaction efficiency involved exploring various solvents.However, the co-solvent system of HFIP with solvents such as CHCl3, Scheme 1. Synthetic of 1,4-benzodiazepiones using [4+3]-cycloaddition with azaoxyallyl cations.

Non-Enantioselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations
To begin our study, our primary objective was to determine the feasibility of the [4+3]-cycloaddition involving 2-amino-β-nitrostyrenes [24] and α-bromohydroxamates.In our initial experiment, we conducted a reaction involving 2-amino-β-nitrostyrene 1a and α-bromohydroxamate 2a, employing Cs 2 CO 3 as a base and HFIP as an additive.This reaction was carried out in toluene at room temperature, resulting in the desired 1,4benzodiazepine-3-ones 3a in an 18% yield (Table 1, entry 1).Despite the initial low yield, these promising results served as a source of motivation to drive further investigations.We embarked on a systematic approach to establish and optimize the reaction conditions for the [4+3]-cycloaddition involving 2-amino-β-nitrostyrene 1a and α-bromohydroxamate 2a.In our quest to identify the optimal reaction conditions for the [4+3]-cycloaddition reaction, we observed a notable improvement when we switched the solvent to CH 2 Cl 2 , resulting in an increased yield of 55% (Table 1, entry 2).Subsequently, we introduced HFIP as a co-solvent.It is worth noting that many cycloadditions involving azaoxyallyl cations have demonstrated enhanced performance in HFIP solutions.This can be attributed to HFIP's distinctive properties, such as its strong hydrogen bond donation and high ionizing power, which effectively stabilize azaoxyallyl cations [25,26].The incorporation of a CH 2 Cl 2 /HFIP co-solvent system significantly improved the yield of 1,4-benzodiazepine-3-one 3a, elevating it to 85%.Moreover, adjusting the solvent concentration to 0.2 M led to a further increase in yield, reaching an impressive 91%.(Table 1, entries 3 and 4).Further efforts to optimize the reaction efficiency involved exploring various solvents.However, the co-solvent system of HFIP with solvents such as CHCl 3 , CH 3 CN, toluene, and THF resulted in inferior yields of the product (Table 1, entries 5-8).Despite thorough exploration of various inorganic and organic bases (Table 1, entries 10-15), it was found that Cs 2 CO 3 consistently delivered the most favorable results.
With the optimized reaction conditions in hand, we embarked on an exploration of the substrate scope and the generality of this reaction (Scheme 2).α-Bromohydroxamates bearing an array of N-protecting groups, including methoxy, ethoxy, tert-butyloxy, and allyloxy, exhibited excellent compatibility with the reaction, yielding the desired products (3a-3e) in yields ranging from good to high (75-91%).A range of 2-amino-β-nitrostyrenes (1b-1i) were employed in the cycloaddition, delivering 1,4-benzodiazepine-3-ones in moderate to good yields (41-83%).Our exploration of substituents positioned at the C4-C6 positions demonstrated a broad tolerance for diverse groups, including halides, -CF 3 , and methyl groups.Moreover, α-bromohydroxamates bearing diethyl, diisopropyl, and cyclohexyl substituents were also successfully accommodated under the reaction conditions, affording the desired products (3n-3p) in good yields (73-79%).CH3CN, toluene, and THF resulted in inferior yields of the product (Table 1, entries 5-8).Despite thorough exploration of various inorganic and organic bases (Table 1, entries 10-15), it was found that Cs2CO3 consistently delivered the most favorable results.With the optimized reaction conditions in hand, we embarked on an exploration of the substrate scope and the generality of this reaction (Scheme 2).α-Bromohydroxamates bearing an array of N-protecting groups, including methoxy, ethoxy, tert-butyloxy, and allyloxy, exhibited excellent compatibility with the reaction, yielding the desired products (3a-3e) in yields ranging from good to high (75-91%).A range of 2-amino-β-nitrostyrenes (1b-1i) were employed in the cycloaddition, delivering 1,4-benzodiazepine-3-ones in moderate to good yields (41-83%).Our exploration of substituents positioned at the C4-C6 positions demonstrated a broad tolerance for diverse groups, including halides, -CF3, and methyl groups.Moreover, α-bromohydroxamates bearing diethyl, diisopropyl, and cyclohexyl substituents were also successfully accommodated under the reaction conditions, affording the desired products (3n-3p) in good yields (73-79%).
The reaction between 2-amino-β-nitrostyrene 1a and α-bromohydroxamate 2a, utilizing Na 2 CO 3 as a base and a bifunctional squaramide-based organocatalyst Ia, was carried out in CF 3 C 6 H 5 at room temperature, yielding the desired enantio-enriched 1,4benzodiazepine-3-one 3a in a 14% yield with a 48% ee (Table 2, entry 1).Although the yield was modest, it confirmed the possibility of enantiomeric discrimination.Subsequently, to enhance both the reaction yield and enantioselectivity, we optimized the reaction conditions.A comprehensive exploration of various inorganic and organic bases was conducted (Table 2, entries 2-7).In terms of yield, Cs 2 CO 3 displayed slightly superior results compared to Na 2 CO 3 , and with respect to enantioselectivity, K 2 CO 3 outperformed Na 2 CO 3 .However, when considering the overall performance, it became evident that Na 2 CO 3 yielded the most promising results.Moving forward, we further investigated various organic solvents, including toluene, CH 2 Cl 2 , CHCl 3 , ClCH 2 CH 2 Cl, THF, and CH 3 CN, employing catalyst Ia.Notably, when utilizing CH 2 Cl 2 as the solvent, both the reaction yield and stereoselectivity were significantly higher compared to the other solvents tested, resulting in a 37% yield and a 78% ee (Table 2, entry 9).In our ongoing effort to optimize the reaction conditions, we conducted a screening of various chiral cinchona-derived squaramide-based catalysts (Figure 2).The cinchonidine-derived squaramide catalyst Ib, yielded results similar to those obtained with the quinine-derived squaramide catalyst Ia.However, the bis(trifluoromethyl)phenylmethylene-squaramide catalysts (Ic and Id) produced inferior results compared to the bis(trifluoromethyl)phenyl-squaramide catalysts (Ia and Ib).Among the bifunctional catalysts evaluated, cinchonidine-derived squaramide III emerged as the optimal choice due to its outstanding reactivity and enantioselectivity (Table 2, entry 17).On the other hand, the cinchona-derived thiourea catalyst IV exhibited good reactivity with a 72% yield, but unfortunately, it did not demonstrate enantioselectivity (Table 2, entry 18; 72% yield, 2% ee).Furthermore, our investigation revealed that the addition of HFIP as an additive in this reaction led to a slight decrease in enantioselectivity, but a notable increase in reactivity.After careful examination, we determined that the optimal reaction conditions entailed employing catalyst III, Na 2 CO 3 as the base, HFIP as the additive, and CH 2 Cl 2 as the solvent (Table 2, entry 22; 64% yield, and 72% ee).
Upon the optimized reaction conditions, the substrate scope and the generality of the 2-amino-β-nitrostyrene and α-bromohydroxamate were investigated, as shown in Scheme 3. α-Bromohydroxamates, featuring a range of N-protecting groups such as methoxy, ethoxy, and allyloxy demonstrated good reactivity and exhibited moderate enantioselectivity (63-71% ee), with only slightly reduced enantioselectivity observed for α-bromohydroxamate having tert-butyloxy group.A variety of 2-amino-β-nitrostyrenes (1b-1i) were utilized in the cycloaddition, yielding enantioenriched 1,4-benzodiazepine-3-ones with moderate to good yields (ranging from 36% to 80%) and enantioselectivities between 42% to 72% ee.Substituents positioned at C4-C6 exhibited a remarkable degree of adaptability, displaying a wide range of tolerance in terms of enantioselectivity for various groups.Regrettably, α-bromohydroxamates bearing diethyl, diisopropyl, and cyclohexyl substituents, which successfully underwent racemic reactions, did not exhibit reactivity in this asymmetric reaction.Finally, the relative and absolute configuration of the proposed 1,4-benzodiazepine-3-ones were determined by X-ray crystallographic analysis of 3a [31].The configurations of the other products were assigned by analogy.demonstrate enantioselectivity (Table 2, entry 18; 72% yield, 2% ee).Furthermore, our investigation revealed that the addition of HFIP as an additive in this reaction led to a slight decrease in enantioselectivity, but a notable increase in reactivity.After careful examination, we determined that the optimal reaction conditions entailed employing catalyst III, Na2CO3 as the base, HFIP as the additive, and CH2Cl2 as the solvent (Table 2, entry 22; 64% yield, and 72% ee).Upon the optimized reaction conditions, the substrate scope and the generality of the 2-amino-β-nitrostyrene and α-bromohydroxamate were investigated, as shown in Scheme 3. α-Bromohydroxamates, featuring a range of N-protecting groups such as methoxy, ethoxy, and allyloxy demonstrated good reactivity and exhibited moderate enantioselectivity (63-71% ee), with only slightly reduced enantioselectivity observed for α-bromohydroxamate having tert-butyloxy group.A variety of 2-amino-β-nitrostyrenes To illustrate the practicality of the [4+3]-cycloaddition, we conducted a one-mmol scale reaction and subsequent synthetic transformations.The scalability of the [4+3]cycloaddition reaction was verified using 1 mmol of 1a and 1f under the optimized reaction conditions, resulting in a modest reduction in yield (47% and 53%, respectively), but with minimal loss of enantioselectivities (Scheme 4).Moreover, we demonstrated the versatility of the synthesized 1,4-benzodiazepine-3-ones 3 through subsequent transformations (Scheme 5).Successfully reducing the nitro group in the 1,4benzodiazepine-3-one products, particularly 3a, was achieved using NiCl2 and NaBH4, in combination with (Boc)2O, yielding product 4 with a respectable 57% yield.Additionally, deprotecting the benzyl group of 3a via palladium-catalyzed hydrogenation produced Nhydroxylamide products 5 in high yield (94%) and a slightly enhanced enantioselectivity (80% ee).To illustrate the practicality of the [4+3]-cycloaddition, we conducted a one-mmol scale reaction and subsequent synthetic transformations.The scalability of the [4+3]cycloaddition reaction was verified using 1 mmol of 1a and 1f under the optimized reaction conditions, resulting in a modest reduction in yield (47% and 53%, respectively), but with minimal loss of enantioselectivities (Scheme 4).Moreover, we demonstrated the versatility of the synthesized 1,4-benzodiazepine-3-ones 3 through subsequent transformations (Scheme 5).Successfully reducing the nitro group in the 1,4-benzodiazepine-3-one products, particularly 3a, was achieved using NiCl 2 and NaBH 4 , in combination with (Boc) 2 O, yielding product 4 with a respectable 57% yield.Additionally, deprotecting the benzyl group of 3a via palladium-catalyzed hydrogenation produced N-hydroxylamide products 5 in high yield (94%) and a slightly enhanced enantioselectivity (80% ee).
Based on our experimental findings and the absolute configuration of 1,4-benzodiazepine-3-ones, as illustrated in Figure 3, we propose a plausible transition state mechanism.In the reaction, the azaoxyallyl cation undergoes deprotonation, and the deprotonated oxygen atom forms a hydrogen bond with the protonated amine in squaramide catalyst III.Concurrently, 1,4-benzodiazepine-3-ones 1a engages with the catalyst through double hydrogen bonding, effectively stabilizing and activating the substrate in a bidentate interaction.This interaction positions the nitrogen atom of 1a to attack the α-carbon of the azaoxyallyl cation.Simultaneously, the nitrogen atom of the azaoxyallyl cation selectively attacks the Si face of the 2-amino-β-nitrostyrene, facilitating an intramolecular attack that leads to the formation of the desired product 3a with an S-configuration.Based on our experimental findings and the absolute configuration of 1,4benzodiazepine-3-ones, as illustrated in Figure 3, we propose a plausible transition state mechanism.In the reaction, the azaoxyallyl cation undergoes deprotonation, and the deprotonated oxygen atom forms a hydrogen bond with the protonated amine in squaramide catalyst III.Concurrently, 1,4-benzodiazepine-3-ones 1a engages with the catalyst through double hydrogen bonding, effectively stabilizing and activating the substrate in a bidentate interaction.This interaction positions the nitrogen atom of 1a to attack the α-carbon of the azaoxyallyl cation.Simultaneously, the nitrogen atom of the azaoxyallyl cation selectively attacks the Si face of the 2-amino-β-nitrostyrene, facilitating an intramolecular attack that leads to the formation of the desired product 3a with an Sconfiguration.Based on our experimental findings and the absolute configuration of 1,4benzodiazepine-3-ones, as illustrated in Figure 3, we propose a plausible transition state mechanism.In the reaction, the azaoxyallyl cation undergoes deprotonation, and the deprotonated oxygen atom forms a hydrogen bond with the protonated amine in squaramide catalyst III.Concurrently, 1,4-benzodiazepine-3-ones 1a engages with the catalyst through double hydrogen bonding, effectively stabilizing and activating the substrate in a bidentate interaction.This interaction positions the nitrogen atom of 1a to attack the α-carbon of the azaoxyallyl cation.Simultaneously, the nitrogen atom of the azaoxyallyl cation selectively attacks the Si face of the 2-amino-β-nitrostyrene, facilitating an intramolecular attack that leads to the formation of the desired product 3a with an Sconfiguration.

Conclusions
In summary, we have established a highly effective [4+3]-cycloaddition reaction involving 2-amino-β-nitrostyrenes and α-bromohydroxamates using Cs2CO3 as a base.This methodology has proven to be a reliable route for the synthesis of 1,4-benzodiazepin-3-ones, consistently delivering good yields.Furthermore, we have achieved an organocatalytic asymmetric [4+3]-cycloaddition employing a bifunctional squaramidebased catalyst.This innovative approach has paved the way for the enantioselective synthesis of chiral 1,4-benzodiazepines, yielding impressive results in terms of both yields and enantioselectivities, (up to 80% yield and 72% ee).The resulting seven-membered benzodiazepin-3-one compounds are anticipated to provide a valuable foundation for the

Procedure for Reduction of 3a
Step 1: To a solution of 3a (39 mg, 0.10 mmol, 1 equiv) in MeOH (1.0 mL, 0.1 M) at 0 • C was added NiCl 2 •6H 2 O (48 mg, 0.20 mmol, 2 equiv).After stirring for 5 min at 0 • C, NaBH 4 (38 mg, 1.0 mmol, 10 equiv) was added in portions to the reaction mixture.The mixture was allowed to stir at room temperature for 1 h.After then, the resulting mixture was quenched with deionized water (1 mL) and added CH 2 Cl 2 (2 mL).The mixture was filtered through the plug of celite and the filtrate was extracted with CH 2 Cl 2 .The combined organic layers were washed with brine, dried (anhydrous Na 2 SO 4 ), and concentrated in vacuo.The crude residue was purified by flash column chromatography with 3% MeOH/EtOAc (with 2% Et 3 N) as eluent to afford nitro reduction products.Step 2: A solution of the crude primary amine in CH 2 Cl 2 (1.0 mL, 0.1 M) was added (Boc) 2 O and stirred for 18 h at room temperature.Then, the resulting mixture was concentrated in vacuo and was purified by flash column chromatography (EtOAc/hexanes = 1:3) as eluent to afford desired product 4 (26 mg, yield 57%) as a white solid.Chiralpak AD-H column and AD-H guard column (5% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); minor-isomer t r = 21.3 min and major-isomer t r = 31.8min.

Procedure for Debenzylation of 3a
A solution of 3a (39 mg, 0.10 mmol) and 5% Pd/C (21 mg, 10 mol%) in EtOAc (1.0 mL, 0.1 M) was stirred under H 2 atmosphere for 6 h at room temperature.After that, the resulting mixture was filtered through the plug of celite and concentrated in vacuo to afford desired product 7 (28 mg, yield 94%) as a white solid.

Conclusions
In summary, we have established a highly effective [4+3]-cycloaddition reaction involving 2-amino-β-nitrostyrenes and α-bromohydroxamates using Cs 2 CO 3 as a base.This methodology has proven to be a reliable route for the synthesis of 1,4-benzodiazepin-3-ones, consistently delivering good yields.Furthermore, we have achieved an organocatalytic asymmetric [4+3]-cycloaddition employing a bifunctional squaramide-based catalyst.This innovative approach has paved the way for the enantioselective synthesis of chiral 1,4benzodiazepines, yielding impressive results in terms of both yields and enantioselectivities, (up to 80% yield and 72% ee).The resulting seven-membered benzodiazepin-3-one compounds are anticipated to provide a valuable foundation for the synthesis of a wide range of diverse compounds.

Figure 3 .
Figure 3.The Plausible transition state of the reaction.

Figure 3 .
Figure 3.The Plausible transition state of the reaction.

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a .
a The reactions were carried out in solvent (1.0 mL) with 1a (0.10 mmol), 2a (0.15 mmol), base (0.20 mmol), and additive.b Isolated yield after chromatographic purification.c In 0.2 M solution.d Using 1.5 equiv of base.

Table 2 .
Optimization of the asymmetric catalytic reaction conditions a .

Table 2 .
Optimization of the asymmetric catalytic reaction conditions a .