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

Abstract

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.

1. Introduction

N,N-Heterocycles are prevalent in various natural products and pharmaceuticals, making them crucial structural elements in medicinal chemistry [1,2]. Among these, 1,4-benzodiazepinone, 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].

We recently reported research detailing synthetic methods for 1,4-benzodiazepinone through the utilization of a [4+3]-annulation approach involving azaoxyallyl cations [20,21,22,23]. We successfully achieved the one-pot synthesis of 1,4-benzodiazepine-3-ones by conducting aza/aza-[4+3]-cycloadditions of α-halohydroxamates with 2-aminophenyl α,β-unsaturated phenyl ketones. This reaction employed Cs₂CO₃ as the base and hexafluoroisopropanol (HFIP) as an additive, resulting in the formation of 1,4-benzodiazepine-3-ones in good yields (Scheme 1a) [20]. We also developed a [4+3]-annulation reaction involving in situ-generated azaoxyallyl cations and isatoic anhydride, leading to the synthesis of seven-membered 1,4-benzodiazepinediones in moderate to good yields. This reaction involves a sequential cascade, encompassing decarboxylative addition of HFIP to isatoic anhydride, addition to azaoxyallyl cation, and intramolecular substitution, ultimately yielding 1,4-benzodiazepinediones (Scheme 1b) [21]. In addition to these advancements, we reported an organocatalytic asymmetric [4+3]-cycloaddition of 2-aminophenyl α,β-unsaturated carbonyls with in situ generated azaoxyallyl cations. In this asymmetric reaction, we obtained enantioenriched functionalized seven-membered 1,4-benzodiazepine-3-ones in good yields and with excellent enantioselectivities (Scheme 1c). Furthermore, several of the resulting compounds displayed promising bioactivity in the prevention of peripheral nerve degeneration [23]. Continuing our exploration of organocatalytic asymmetric [4+3]-cycloaddition reactions for the synthesis of enantioenriched 1,4-benzodiazepine-3-ones, we present our achievement in the asymmetric [4+2]-cycloaddition of 2-amino-β-nitrostyrenes and α-bromohydroxamates (Scheme 1d). We anticipate that the resulting compounds will serve as a valuable foundation for the synthesis of diverse compounds, potentially enhancing their bioactivity by facilitating the conversion of the nitro group.

2. Results and Discussion

2.1. 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 Cs₂CO₃ as a base and HFIP as an additive. This reaction was carried out in toluene at room temperature, resulting in the desired 1,4-benzodiazepine-3-ones 3a in an 18% yield (

Table 1. Optimization of the reaction conditions ^a.

Entry	Base	Additive	Solvent	Time (h)	Yield (%) b
1	Cs2CO3	HFIP (5 equiv)	CF3C6H5	24	18
2	Cs2CO3	HFIP (5 equiv)	CH2Cl2	2	55
3	Cs2CO3	-	CH2Cl2/HFIP	2	85
4 c	Cs2CO3	-	CH2Cl2/HFIP	1	91
5 c	Cs2CO3	-	CHCl3/HFIP	1	90
6 c	Cs2CO3	-	CH3CN/HFIP	2	35
7	Cs2CO3	-	toluene/HFIP	2	86
8	Cs2CO3	-	THF/HFIP	1	69
9 c,d	Cs2CO3	-	CH2Cl2/HFIP	1	81
10 c	K2CO3	-	CH2Cl2/HFIP	1	62
11 c	Na2CO3	-	CH2Cl2/HFIP	2	34
12 c	Et3N	-	CH2Cl2/HFIP	1	84
13 c	DABCO	-	CH2Cl2/HFIP	2	64
14 c	DMAP	-	CH2Cl2/HFIP	1	76
15 c	DBU	-	CH2Cl2/HFIP	2	83

^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.

, 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 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 1,4-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 CHCl₃, 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%).

2.2. Enantioselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations

Having successfully pioneered the initial instance of [4+3]-cycloaddition between 2-amino-β-nitrostyrenes and azaoxyallyl cations, our research focus naturally transitioned towards developing an enantioselective reaction. This shift holds the promise of opening a new pathway to obtain enantioenriched chiral 1,4-benzodiazepine-3-ones. We envisioned achieving enantioselective [4+3]-cycloaddition through the use of a suitable bifunctional squaramide-based or thiourea-based organocatalyst, facilitating precise hydrogen bonding interactions [27,28,29,30].

The reaction between 2-amino-β-nitrostyrene 1a and α-bromohydroxamate 2a, utilizing Na₂CO₃ as a base and a bifunctional squaramide-based organocatalyst Ia, was carried out in CF₃C₆H₅ at room temperature, yielding the desired enantio-enriched 1,4-benzodiazepine-3-one 3a in a 14% yield with a 48% ee (

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

Entry	Cat.	Base	Solvent	Yield (%) b	Ee c
1	Ia	Na2CO3	CF3C6H5	14	48
2	Ia	K2CO3	CF3C6H5	11	60
3	Ia	Cs2CO3	CF3C6H5	19	6
4	Ia	Et3N	CF3C6H5	18	6
5	Ia	DIPEA	CF3C6H5	27	6
6	Ia	DABCO	CF3C6H5	10	22
7	Ia	DMAP	CF3C6H5	11	4
8	Ia	Na2CO3	Toluene	24	70
9	Ia	Na2CO3	CH2Cl2	37	78
10	Ia	Na2CO3	CHCl3	35	76
11	Ia	Na2CO3	ClCH2CH2Cl	34	74
12	Ia	Na2CO3	THF	15	4
13	Ia	Na2CO3	CH3CN	33	2
14	Ib	Na2CO3	CH2Cl2	37	78
15	IIa	Na2CO3	CH2Cl2	23	60
16	IIb	Na2CO3	CH2Cl2	19	56
17	III	Na2CO3	CH2Cl2	38	80
18	IV	Na2CO3	CH2Cl2	72	2
19 d	III	Na2CO3	CH2Cl2	73	58
20 e	III	Na2CO3	CH2Cl2	63	64
21 f	III	Na2CO3	CH2Cl2	61	72
22 f,g	III	Na2CO3	CH2Cl2	64	72

^a The reactions were carried out in solvent (1.0 mL) with 1a (0.10 mmol), 2a (0.20 mmol), base (0.20 mmol), and catalyst (10 mol%). ^b Isolated yield after chromatographic purification. ^c Determined by chiral HPLC. ^d Added 5 equiv of HFIP. ^e Added 3 equiv of HFIP. ^f Added 1.2 equiv of HFIP. ^g Using 2a (0.30 mmol) and Na₂CO₃ (0.25 mmol).

, 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, Cs₂CO₃ displayed slightly superior results compared to Na₂CO₃, and with respect to enantioselectivity, K₂CO₃ outperformed Na₂CO₃. However, when considering the overall performance, it became evident that Na₂CO₃ yielded the most promising results. Moving forward, we further investigated various organic solvents, including toluene, CH₂Cl₂, CHCl₃, ClCH₂CH₂Cl, THF, and CH₃CN, employing catalyst Ia. Notably, when utilizing CH₂Cl₂ 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, 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 (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.

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 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 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.

3. Experimental

3.1. General Information

Prior to usage, organic solvents (Daejung Chemicals & Metals Co, Siheung, Republic of Korea) underwent distillation. Under reduced pressure, organic solutions were concentrated using a rotary evaporator. Forced-flow chromatography on Merk silica gel 60 achieved chromatographic purification of products. EM Reagents 0.25 mm silica gel 60-F plates (Merk, Rahway, NJ, USA) were utilized for Thin-layer chromatography (TLC). Visualization of developed chromatograms occurred through fluorescence quenching and anisaldehyde stain. Recording at 400 MHz for ¹H, 100 MHz for ¹³C, and 176 MHz for ¹⁹F, ¹H, ¹³C, and ¹⁹F NMR spectra were internally referenced to residual protic solvent signals. ¹H NMR data include chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad singlet, dd = doublet of doublets, dt = doublet of triplets, qd = quartet of doublets, ddd = doublet of doublet of doublets, and m = multiplet), coupling constant (Hz), and integration. Chemical shift is used to report ¹³C NMR data. IR spectra were recorded on an FT IR spectrometer (Bruker, Karlsruhe, Germany). High-resolution mass spectra (HRMS) were obtained using a double-focusing mass spectrometer with EI-magnetic sector (Jeol Ltd., Tokyo, Japan). The crystal structure was determined by a single-crystal diffractometer (a Bruker D8 Venture PHOTON III M14 diffractometer) (Bruker, Karlsruhe, Germany) at the Western Seoul Center of Korea Basic Science Institute. Enantiomeric excesses were determined using an HPLC instrument with Chiralpak columns (Daicel Corporation, Tokyo, Japan), as indicated. α-Bromohydroxamates [32,33,34], 2-amino-β-nitrostyrens [24], and organocatalysts [35,36,37] were prepared according to the literature.

3.2. General Procedure I for the [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with α-Bromohydroxamates

To a solution of 2-amino-β-nitrostyrene 1 (0.20 mmol, 1 equiv) and α-bromohydroxamate 2 (0.30 mmol, 1.5 equiv in CH₂Cl₂/HFIP (1:1, 1.0 mL, 0.2 M) was added Cs₂CO₃ (0.40 mmol, 2 equiv) at 0 °C. The reaction mixture was allowed to stir at room temperature. After stirring for 1 h, the resulting mixture was filtered through the plug of celite. The filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography with EtOAc/hexanes as eluent to afford desired product 3 (The spectra can be found in Supplementary Materials).

4-(Benzyloxy)-7-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3a). Following the general procedure I; 71 mg, yield 91%, White solid; m.p. 145–147 °C; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.37 (m, 5H), 7.18 (dd, J = 8.3, 2.4 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 5.24–5.12 (m, 1H), 4.96 (s, 2H), 4.86–4.75 (m, 2H), 3.12 (s, 1H), 1.63 (s, 3H), 1.21 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.7, 142.8, 134.9, 130.5, 130.4, 130.2, 129.4, 129.0, 128.9, 128.6, 124.6, 76.6, 75.0, 65.8, 63.5, 29.7, 27.7; IR (neat) 3338, 2922, 2854, 1666, 1551, 1489, 1454, 1388, 1285, 1230, 1197, 1000 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₂₀ClN₃O₄: 389.1142 Found: 389.1123.

7-Chloro-4-methoxy-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3b). Following the general procedure I; 53 mg, yield 73%, White solid; m.p. 52–54 °C; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, J = 2.3 Hz, 1H), 7.28–7.23 (m, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.34–5.15 (m, 2H), 5.04 (dd, J = 11.4, 4.5 Hz, 1H), 3.78 (s, 3H), 3.23 (s, 1H), 1.61 (s, 3H), 1.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.6, 143.1, 130.7, 130.0, 129.15, 129.11, 125.0, 75.5, 64.2, 63.5, 62.0, 29.8, 27.3; IR (neat) 3313, 2974, 2932, 1650, 1549, 1491, 1449, 1424, 1377, 1307, 1197, 1024 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₃H₁₆ClN₃O₄: 313.0829 Found: 313.0806.

7-Chloro-4-ethoxy-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3c). Following the general procedure I; 56 mg, yield 85%, White solid; m.p. 118–120 °C; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, J = 2.3 Hz, 1H), 7.27–7.23 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.30 (dd, J = 12.1, 8.8 Hz, 1H), 5.18 (dd, J = 8.8, 4.9 Hz, 1H), 5.04 (dd, J = 12.1, 4.9 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.22 (s, 1H), 1.61 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.7, 143.1, 130.7, 130.1, 129.1, 129.0, 124.9, 75.3, 70.1, 64.8, 63.4, 29.7, 27.6, 13.6; IR (neat) 3309, 2980, 2931, 1644, 1555, 1490, 1379, 1307, 1261, 1194, 1026 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₄H₁₈ClN₃O₄: 327.0986 Found: 327.1006.

4-(tert-Butoxy)-7-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3d). Following the general procedure I; 54 mg, yield 75%, White solid; m.p. 129–131 °C; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.30–7.24 (m, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.38 (dd, J = 12.3, 9.7 Hz, 1H), 5.13 (dd, J = 9.7, 4.2 Hz, 1H), 4.94 (dd, J = 12.4, 4.1 Hz, 1H), 3.35 (s, 1H), 1.60 (s, 3H), 1.32 (s, 9H), 1.22 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 176.1, 143.3, 130.7, 130.6, 128.5, 127.3, 124.2, 84.1, 74.0, 67.1, 63.0, 28.7, 28.6, 27.2; IR (neat) 3358, 2978, 2934, 1682, 1547, 1479, 1447, 1421, 1374, 1310, 1198, 1157, 1097, 977 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₆H₂₂ClN₃O₄: 355.1299 Found: 355.1281.

4-(Allyloxy)-7-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3e). Following the general procedure I; 51 mg, yield 75%, Colorless gum; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J = 1.3 Hz, 1H), 7.26–7.24 (m, 1H), 6.87–6.77 (m, 1H), 6.05 (ddt, J = 17.4, 9.8, 6.7 Hz, 1H), 5.39–5.26 (m, 3H), 5.17 (dd, J = 8.9, 4.8 Hz, 1H), 5.03 (dd, J = 12.1, 4.8 Hz, 1H), 4.45 (dd, J = 6.7, 1.0 Hz, 2H), 3.18 (s, 1H), 1.62 (s, 3H), 1.19 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.8, 143.1, 131.8, 130.7, 130.3, 129.2, 128.9, 124.9, 121.8, 75.8, 75.2, 65.3, 63.5, 29.7, 27.6; IR (neat) 3311, 2973, 2928, 1650, 1549, 1491, 1451, 1422, 1377, 1306, 1285, 1198, 995 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₅H₁₈ClN₃O₄: 339.0986 Found: 339.0963.

4-(Benzyloxy)-7-bromo-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3f). Following the general procedure I; 72 mg, yield 83%, White solid; m.p. 102–104 °C; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.42 (m, 1H), 7.42–7.36 (m, 4H), 7.32 (dd, J = 8.2, 2.2 Hz, 1H), 6.76–6.61 (m, 2H), 5.22–5.10 (m, 1H), 4.95 (s, 2H), 4.86–4.74 (m, 2H), 3.13 (s, 1H), 1.63 (s, 3H), 1.21 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.6, 143.3, 134.9, 133.4, 133.0, 130.4, 129.4, 129.0, 128.9, 125.0, 116.2, 76.5, 75.0, 65.7, 63.5, 29.6, 27.8; IR (neat) 3339, 2969, 2924, 1646, 1549, 1488, 1455, 1376, 1282, 1196, 999 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₂₀BrN₃O₄: 433.0637 Found: 433.0653.

4-(Benzyloxy)-7-fluoro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3g). Following the general procedure I; 44 mg, yield 58%, White solid; m.p. 98–100 °C; R_f 0.3 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.36 (m, 5H), 6.93 (td, J = 8.3, 2.9 Hz, 1H), 6.77 (dd, J = 8.6, 4.7 Hz, 1H), 6.39 (dd, J = 8.3, 2.9 Hz, 1H), 5.21 (dd, J = 11.8, 8.5 Hz, 1H), 4.95 (d, J = 1.4 Hz, 2H), 4.80 (ddd, J = 16.6, 12.5, 4.9 Hz, 2H), 3.07 (s, 1H), 1.62 (s, 3H), 1.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 173.0, 158.7 (d, J¹ = 244.1 Hz), 140.2 (d, J⁴ = 2.7 Hz), 134.9, 130.3, 129.4, 129.0, 128.8 (d, J³ = 8.0 Hz), 124.8 (d, J³ = 8.1 Hz), 117.2 (d, J² = 22.3 Hz), 117.1 (d, J² = 23.6 Hz), 76.5, 75.1, 65.8 (d, J⁴ = 1.7 Hz), 63.5, 29.7, 27.4; ¹⁹F NMR (376 MHz, CDCl₃) δ -118.93; IR (neat) 3339, 2986, 2925, 1667, 1552, 1495, 1458, 1407, 1387, 1288, 1202, 1149, 999 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₂₀FN₃O₄: 373.1438 Found: 373.1448.

4-(Benzyloxy)-8-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3h). Following the general procedure I; 64 mg, yield 82%, White solid; m.p. 133–135 °C; R_f 0.4 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.35 (m, 5H), 6.89 (dd, J = 8.1, 2.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.12 (dd, J = 12.0, 9.1 Hz, 1H), 4.95 (s, 2H), 4.85 (dd, J = 9.1, 4.8 Hz, 1H), 4.76 (dd, J = 12.1, 4.8 Hz, 1H), 3.21 (s, 1H), 1.63 (s, 3H), 1.23 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.8, 145.5, 136.1, 135.0, 131.4, 130.3, 129.3, 128.9, 125.4, 123.9, 123.3, 76.5, 75.0, 65.6, 63.5, 29.6, 27.7; IR (neat) 3336, 3001, 2977, 1657, 1595, 1548, 1454, 1416, 1383, 1297, 1201, 1088, 1002 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₂₀ClN₃O₄: 389.1142 Found: 389.1163.

4-(Benzyloxy)-8-bromo-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3i). 66 mg, yield 76%, White solid; m.p. 138–140 °C; R_f 0.5 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.35 (m, 5H), 7.04 (dd, J = 8.0, 1.9 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 12.1, 9.0 Hz, 1H), 4.95 (s, 2H), 4.84 (dd, J = 9.1, 4.8 Hz, 1H), 4.75 (dd, J = 12.1, 4.8 Hz, 1H), 3.21 (s, 1H), 1.63 (s, 3H), 1.23 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.7, 145.6, 134.9, 131.6, 130.3, 129.3, 128.9, 126.8, 126.2, 125.9, 124.1, 76.5, 74.9, 65.7, 63.5, 29.6, 27.8; IR (neat) 3337, 3000, 2976, 1651, 1590, 1548, 1453, 1416, 1380, 1309, 1228, 1200, 1079, 1002 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₂₀BrN₃O₄: 433.0637 Found: 433.0616.

4-(Benzyloxy)-2,2-dimethyl-5-(nitromethyl)-8-(trifluoromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3j). Following the general procedure I; 60 mg, yield 71%, White solid; m.p. 138–140 °C; R_f 0.4 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.35 (m, 5H), 7.17 (dd, J = 7.9, 1.7 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 5.15 (dd, J = 12.4, 9.2 Hz, 1H), 4.96 (s, 2H), 4.93 (dd, J = 9.1, 4.8 Hz, 1H), 4.78 (dd, J = 12.3, 4.7 Hz, 1H), 3.35 (s, 1H), 1.66 (s, 3H), 1.23 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.7, 144.8, 134.9, 132.8 (q, J² = 32.8 Hz), 131.1, 130.6, 130.3, 129.4, 129.0, 123.4 (q, J¹ = 272.6 Hz). 120.5 (q, J³ = 3.8 Hz), 119.9 (q, J³ = 3.6 Hz), 76.6, 74.8, 65.8, 63.6, 29.6, 27.8; ¹⁹F NMR (376 MHz, CDCl₃) δ -62.8; IR (neat) 3339, 2976, 1650, 1550, 1454, 1414, 1379, 1327, 1284, 1232, 1203, 1163, 1121, 1075 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₀H₂₀F₃N₃O₄: 423.1406 Found: 423.1396.

4-(Benzyloxy)-2,2,8-trimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3k). Following the general procedure I; 30 mg, yield 41%, White solid; m.p. 110–112 °C; R_f 0.4 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.41 (m, 2H), 7.41–7.35 (m, 3H), 6.73 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 6.67–6.59 (m, 2H), 5.15 (dd, J = 11.8, 8.9 Hz, 1H), 4.95 (s, 2H), 4.91 (dd, J = 8.9, 5.0 Hz, 1H), 4.80 (dd, J = 11.8, 5.0 Hz, 1H), 3.05 (s, 1H), 2.27 (s, 3H), 1.63 (s, 3H), 1.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 173.3, 144.2, 140.9, 135.1, 130.22, 130.19, 129.2, 128.9, 124.5, 124.0 (two peaks overlapping), 76.4, 75.6, 66.0, 63.4, 29.9, 27.6, 21.3; IR (neat) 3335, 2919, 1659, 1620, 1548, 1454, 1414, 1380, 1287, 1204, 1184, 1000 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₀H₂₃N₃O₄: 369.1689 Found: 369.1667.

4-(Benzyloxy)-2,2,9-trimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3l). Following the general procedure I; 63 mg, yield 75%, White solid; m.p. 152–154 °C; R_f 0.4 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.41 (m, 2H), 7.41–7.34 (m, 3H), 7.18–7.11 (m, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.62 (dd, J = 7.6, 1.5 Hz, 1H), 5.15 (dd, J = 11.9, 8.8 Hz, 1H), 5.00–4.92 (m, 3H), 4.82 (dd, J = 11.9, 5.0 Hz, 1H), 3.19 (s, 1H), 2.22 (s, 3H), 1.69 (s, 3H), 1.18 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 173.2, 142.8, 135.1, 132.2, 130.2, 130.0, 129.2, 128.9, 128.5, 127.4, 123.4, 76.4, 75.8, 66.5, 63.7, 29.9, 26.8, 17.5; IR (neat) 3344, 2987, 2972, 1658, 1543, 1469, 1453, 1373, 1303, 1241, 1214, 1175, 986 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₀H₂₃N₃O₄: 369.1689 Found: 369.1700.

4-(Benzyloxy)-6-bromo-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3m). Following the general procedure I; 48 mg, yield 55%, White solid; m.p. 68–70 °C; R_f 0.4 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.44 (m, 2H), 7.42–7.30 (m, 4H), 7.12 (t, J = 7.9 Hz, 1H), 6.84 (dd, J = 7.8, 1.1 Hz, 1H), 6.13 (dd, J = 7.9, 5.7 Hz, 1H), 5.26 (dd, J = 12.1, 7.9 Hz, 1H), 5.07–4.92 (m, 3H), 3.27 (s, 1H), 1.63 (s, 3H), 1.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.4, 146.3, 134.6, 131.4, 129.9, 129.1, 128.8, 128.7, 128.1, 124.6, 123.4, 76.7, 75.5, 63.7, 63.7, 30.0, 27.4; IR (neat) 3298, 2970, 2919, 1650, 1548, 1453, 1415, 1374, 1305, 1198, 989, 969 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₂₀BrN₃O₄: 433.0637 Found: 433.0653.

4-(Benzyloxy)-7-chloro-2,2-diethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3n). Following the general procedure I; 61 mg, yield 73%, White solid; m.p. 188–190 °C; R_f 0.4 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.36 (m, 5H), 7.16 (dd, J = 8.3, 2.4 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.13 (dd, J = 12.2, 8.8 Hz, 1H), 4.96 (d, J = 1.0 Hz, 2H), 4.85 (dd, J = 12.2, 5.0 Hz, 1H), 4.77 (dd, J = 8.9, 5.0 Hz, 1H), 3.27 (s, 1H), 2.25 (dq, J = 14.6, 7.4 Hz, 1H), 1.65 (dt, J = 14.9, 7.5 Hz, 1H), 1.54 (dq, J = 14.4, 7.2 Hz, 1H), 1.44 (dq, J = 14.7, 7.4 Hz, 1H), 1.08 (t, J = 7.3 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.8, 143.0, 143.0, 134.9, 130.4, 130.15, 130.13, 129.4, 129.0, 128.2, 128.0, 124.2, 75.4, 70.2, 65.8, 32.01, 31.99, 9.1, 7.6; IR (neat) 3343, 2966, 2935, 2878, 1666, 1551, 1485, 1454, 1383, 1279, 1227, 1182, 1005 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₁H₂₄ClN₃O₄: 417.1455 Found: 417.1452.

4-(Benzyloxy)-7-chloro-5-(nitromethyl)-2,2-dipropyl-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3o). Following the general procedure I; 71 mg, yield 79%, White solid; m.p. 98–100 °C; R_f 0.7 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.49–7.34 (m, 5H), 7.16 (dd, J = 8.3, 2.4 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 5.14 (dd, J = 12.0, 8.7 Hz, 1H), 4.96 (s, 2H), 4.87–4.75 (m, 2H), 3.28 (s, 1H), 2.20 (td, J = 12.6, 3.1 Hz, 1H), 1.73–1.52 (m, 2H), 1.52–1.35 (m, 2H), 1.35–1.18 (m, 3H), 0.96 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.9, 143.0, 134.8, 130.41, 130.38, 130.1, 129.4, 129.0, 128.2, 128.1, 124.1, 76.8, 75.3, 69.8, 65.7, 42.0, 41.7, 18.0, 16.3, 14.5, 14.3; IR (neat) 3341, 2967, 2872, 1655, 1549, 1483, 1453, 1431, 1381, 1284, 1178, 1014 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₃H₂₈ClN₃O₄: 445.1768 Found: 445.1765.

4-(Benzyloxy)-7-chloro-5-(nitromethyl)-4,5-dihydrospiro[benzo[e][1,4]diazepine-2,1’-cyclohexan]-3(1H)-one (3p). Following the general procedure I; 66 mg, yield 77%, White solid; m.p. 125–127 °C; R_f 0.5 (30% ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.35 (m, 5H), 7.18 (dd, J = 8.3, 2.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 5.19–5.06 (m, 1H), 4.94 (s, 2H), 4.83–4.71 (m, 2H), 3.71 (s, 1H), 2.41 (td, J = 13.9, 4.7 Hz, 1H), 1.92–1.79 (m, 2H), 1.79–1.60 (m, 2H), 1.59–1.47 (m, 1H), 1.47–1.24 (m, 4H); ¹³C NMR (101 MHz, CDCl₃) δ 173.6, 142.0, 135.0, 130.4, 130.3, 130.2, 129.3, 129.0 (two peaks overlapping), 128.5, 124.3, 76.5, 75.1, 65.8, 65.3, 34.2, 32.2, 24.6, 21.3, 20.6; IR (neat) 3385, 2932, 2859, 1656, 1541, 1492, 1455, 1436, 1379, 1318, 1267, 1178, 980 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₂H₂₄ClN₃O₄: 429.1455 Found: 429.1484.

3.3. General Procedure II for the Asymmetric [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with α-Bromohydroxamates

A solution of 2-amino-β-nitrostyrene 1 (0.10 mmol, 1 equiv), α-bromohydroxamate 2 (0.2 mmol, 2 equiv), HFIP (0.12 mmol, 1.2 equiv), and catalyst III (0.01 mmol, 0.1 equiv) in CH₂Cl₂ (1.0 mL, 0.1 M) were stirred for 5 min at 0 °C, then added Na₂CO₃ (0.15 mmol, 1.5 equiv) at 0 °C and allowed to stir at room temperature. After stirring for 1 h and then again for 1 more hours, α-bromohydroxamate 2 (0.05 mmol, 0.5 equiv) and Na₂CO₃ (0.05 mmol, 0.5 equiv) were added to the reaction mixture twice. After stirring for an additional 22 h, the resulting mixture was filtered through the plug of celite. The filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography with EtOAc/hexanes as eluent to afford the desired product 3. The enantiomeric ratio was determined using HPLC analysis.

(S)-4-(Benzyloxy)-7-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3a). Following the general procedure II; 25 mg, yield 64%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{24}$ = +150.7 (c = 0.91, CHCl₃); 72% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 13.8 min and minor-isomer t_r = 42.0 min.

(S)-7-Chloro-4-methoxy-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3b). Following the general procedure II; 23 mg, yield 73%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{22}$ = +93.8 (c = 0.84, CHCl₃); 63% ee; Chiralpak IA column and IA guard column (20% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 8.7 min and minor-isomer t_r = 18.6 min.

(S)-7-Chloro-4-ethoxy-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3c). Following the general procedure II; 22 mg, yield 66%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{23}$ = +103.2 (c = 0.62, CHCl₃); 67% ee; Chiralpak IA column and IA guard column (20% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 7.6 min and minor-isomer t_r = 17.9 min.

(S)-4-(tert-butoxy)-7-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3d). Following the general procedure II; 23 mg, yield 65%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{24}$ = +16.6 (c = 0.84, CHCl₃); 23% ee; Chiralpak IA column and IA guard column (2% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 19.9 min and minor-isomer t_r = 36.5 min.

(S)-4-(Allyloxy)-7-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3e). Following the general procedure II; 22 mg, yield 66%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{24}$ = +91.8 (c = 0.64, CHCl₃); 71% ee; Chiralpak IA column and IA guard column (30% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 6.9 min and minor-isomer t_r = 14.1 min.

(S)-4-(Benzyloxy)-7-bromo-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3f). Following the general procedure II; 28 mg, yield 65%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +130.5 (c = 1.07, CHCl₃); 72% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 14.2 min and minor-isomer t_r = 42.1 min.

(S)-4-(Benzyloxy)-7-fluoro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3g). Following the general procedure II; 14 mg, yield 36%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +102.5 (c = 0.48, CHCl₃); 69% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 13.6 min and minor-isomer t_r = 42.3 min.

(S)-4-(Benzyloxy)-8-chloro-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3h). Following the general procedure II; 27 mg, yield 68%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +158.8 (c = 0.86, CHCl₃); 71% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 13.2 min and minor-isomer t_r = 24.7 min.

(S)-4-(Benzyloxy)-8-bromo-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3i). Following the general procedure II; 29 mg, yield 66%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +146.3 (c = 0.86, CHCl₃); 71% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 13.6 min and minor-isomer t_r = 24.0 min.

(S)-4-(Benzyloxy)-2,2-dimethyl-5-(nitromethyl)-8-(trifluoromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3j). Following the general procedure II; 24 mg, yield 57%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +121.3 (c = 0.71, CHCl₃); 72% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 10.5 min and minor-isomer t_r = 14.6 min.

(S)-4-(Benzyloxy)-2,2,8-trimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3k). Following the general procedure II; 16 mg, yield 44%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +136.9 (c = 0.47, CHCl₃); 67% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 12.8 min and minor-isomer t_r = 27.0 min.

(S)-4-(Benzyloxy)-2,2,9-trimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3l). Following the general procedure II; 30 mg, yield 80%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{25}$ = +148.0 (c = 0.93, CHCl₃); 71 ee; Chiralcel OJ-H column and OJ-H guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); minor-isomer t_r = 28.9 min and major-isomer t_r = 35.6 min.

(S)-4-(Benzyloxy)-6-bromo-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (3m). Following the general procedure II; 19 mg, yield 43%, ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{26}$ = +44.6 (c = 0.68, CHCl₃); 42% ee; Chiralpak IA column and IA guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 13.7 min and minor-isomer t_r = 28.3 min.

3.4. Procedure for a One-mmol Scale Synthesis of 3a

A solution of 2-amino-β-nitrostyrene 1a (199 mg, 1.0 mmol), α-bromohydroxamate 2a (544 mg, 2.0 mmol), HFIP (0.13 mL, 1.2 mmol), and catalyst III (60 mg, 0.10 mmol) in CH₂Cl₂ (10 mL, 0.1 M) were stirred for 5 min at 0 °C, then added Na₂CO₃ (159 mg, 1.5 mmol) at 0 °C and allowed to stir at room temperature. After stirring for 1 h and then again for 1 more hour, α-bromohydroxamate 2 (136 mg, 0.5 mmol), and Na₂CO₃ (53 mg, 0.5 mmol) were added to the reaction mixture twice. After stirring for an additional 22 h, the resulting mixture was filtered through the plug of celite. The filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (EtOAc/hexanes = 1:4) as eluent to afford the desired product 3a (183 mg, 47% yield, 72% ee) as a white solid.

3.5. Procedure for a One-mmol Scale Synthesis of 3f

A solution of 2-amino-β-nitrostyrene 1f (243 mg, 0.10 mmol), α-bromohydroxamate 2a (544 mg, 2.0 mmol), HFIP (0.13 mL, 1.2 mmol), and catalyst III (60 mg, 0.10 mmol) in CH₂Cl₂ (10 mL, 0.1 M) were stirred for 5 min at 0 °C, then added Na₂CO₃ (159 mg, 1.5 mmol) at 0 °C and allowed to stir at room temperature. After stirring for 1 hour and then again for 1 more hour, α-bromohydroxamate 2 (136 mg, 0.5 mmol) and Na₂CO₃ (53 mg, 0.5 mmol) were added to the reaction mixture twice. After stirring for an additional 22 h, the resulting mixture was filtered through the plug of celite. The filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (EtOAc/hexanes = 1:4) as eluent to afford the desired product 3f (229 mg, 53% yield, 70 % ee) as a white solid.

3.6. 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 NiCl₂•6H₂O (48 mg, 0.20 mmol, 2 equiv). After stirring for 5 min at 0 °C, NaBH₄ (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 CH₂Cl₂ (2 mL). The mixture was filtered through the plug of celite and the filtrate was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried (anhydrous Na₂SO₄), and concentrated in vacuo. The crude residue was purified by flash column chromatography with 3% MeOH/EtOAc (with 2% Et₃N) as eluent to afford nitro reduction products. Step 2: A solution of the crude primary amine in CH₂Cl₂ (1.0 mL, 0.1 M) was added (Boc)₂O 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.

tert-Butyl (S)-((4-(benzyloxy)-7-chloro-2,2-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)methyl)carbamate (4). ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{24}$ = +103.5 (c = 0.85, CHCl₃); 72% ee; White solid; m.p. 76–78 °C; R_f 0.5 (50% EtOAc in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dtd, J = 13.4, 7.7, 5.8 Hz, 5H), 7.10 (dd, J = 8.3, 2.4 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 4.92 (s, 2H), 4.84 (d, J = 6.5 Hz, 1H), 4.35 (t, J = 7.1 Hz, 1H), 3.80–3.64 (m, 2H), 3.10 (s, 1H), 1.61 (s, 3H), 1.36 (s, 9H), 1.22 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 172.3, 155.8, 143.1, 135.2, 131.1, 130.2, 129.7, 129.3, 128.9, 128.7, 128.1, 124.1, 79.4, 76.0, 67.8, 63.0, 42.7, 29.7, 28.4, 28.0; IR (neat) 3316, 2973, 2929, 2865, 1698, 1633, 1492, 1453, 1392, 1365, 1248, 1164, 995 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₂₄H₃₀ClN₃O₄: 459.1925 Found: 459.1903; 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 = 31.8 min.

3.7. 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 H₂ 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.

(S)-7-Chloro-4-hydroxy-2,2-dimethyl-5-(nitromethyl)-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (5). ${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{24}$ = +133.9 (c = 0.96, CHCl₃); 80% ee; White solid; m.p. 135–137 °C; R_f 0.4 (50% Ethyl acetate in hexanes); ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 7.34–7.26 (m, 2H), 6.85 (d, J = 8.2 Hz, 1H), 5.41 (dd, J = 8.4, 5.5 Hz, 1H), 5.16 (dd, J = 12.4, 8.4 Hz, 1H), 5.07 (dd, J = 12.4, 5.6 Hz, 1H), 3.20 (s, 1H), 1.64 (s, 3H), 1.21 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.0, 142.6, 130.9, 130.3, 129.5, 128.7, 125.3, 75.3, 62.4, 61.8, 29.5, 27.3; IR (neat) 3339, 2920, 2853, 1608, 1546, 1492, 1431, 1377, 1320, 1259, 1198, 1093,1011 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₂H₁₄ClN₃O₄: 299.0673 Found: 299.0675; Chiralcel OD-H column and OD-H guard column (10% EtOH:hexanes, 1.0 mL/min flow, λ = 254 nm); major-isomer t_r = 14.7 min and minor-isomer t_r = 22.8 min.

4. 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 squaramide-based 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 synthesis of a wide range of diverse compounds.