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• Benzazepines are structural motifs within a wide variety of biologically and pharmacologically significant compounds (Fig. 1) [1–7]. For example, a benzazepine moiety is a well-known pharmacophore that is present in several marketed tricyclic antidepressant drugs, including tienopramine (Ⅰ) and amezepine (Ⅱ) [4]. Mozavaptan (Ⅲ), as a benzazepine derivative, is an orally active nonpeptide selective vasopressin V₂-receptor antagonist with an IC₅₀ of 14 nmol/L [5]. Moreover, benazepril (Ⅳ) is a nonsulfhydryl ACE (angiotensin converting enzyme) inhibitor prodrug, which is converted in vivo to its active form, benazeprilat [6]. Compound Ⅴ, is a potent and selective inhibitor of γ-secretase, producing inhibitory activity of Notch signaling in tumor cells [7]. Inspired by the significance of seven-membered nitrogen-heterocycles, many methods have been developed in the past decades [2,3,8–11]. However, most of these methods require harsh reaction conditions or starting materials that are synthesized in several steps. Besides, most of these reports focus on the developments in transition metal-mediated reactions as the key step. Therefore, the development of a general and facile approach with readily accessible starting materials and inexpensive catalysts remains highly desirable.

  Figure 1

  

  Figure 1.  Importance of benzazepines: Selected natural products and pharmaceutical agents.

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  Organocatalytic annulations, especially Lewis base-catalyzed annulations of allenes have been one of the most powerful synthetic strategies for the synthesis of various heterocyclic compounds, especially in the preparation of biologically active natural products and pharmaceutical compounds [12–21]. Among those catalysis, tertiary amines have proven to be effective catalysts for a range of synthetic transformations [14,16]. The zwitterionic dipole formed from different allenes may exist in different isomeric forms. For example, the [β, γ]-[2 + 2] cyclizations of allenes with imines [15–19], ketones [20–22] or azodicarboxylates [23] provided an easy access to the synthesis of four-membered ring (Scheme 1, path a). Tertiary amines-catalyzed [2 + 4] annulations of allenes with ketene derivatives [31–39] or ketene imine derivatives [40,41], provided six-membered ring heterocyclic compounds (Scheme 1, paths b and c). Similarly, the [α, β]-[2 + 4] cyclizations of allenes with salicylaldehydes [42] or salicyl N-tosylimines [43], provided highly functionalized chromene derivatives (Scheme 1, path d). In 2010, Tong's group reported a novel β'-acetoxy allenoate [44]. Based on this, [β, β']-[3 + 3] cycloadditions of β'-acetoxy allenoates provided a wide range of pyran [45,46] or thiapyran derivatives (Scheme 1, path e) [47]. Besides, other tertiary amine-catalyzed cycloadditions of allenes could also provide five-membered ring heterocyclic compounds [48–54]. In the past decades, although huge progress involving tertiary amines-promoted cycloaddition of allenes has been made in the construction of heterocyclic compounds, almost all of these studies focused on the synthesis of four-, five- or six-membered rings [14,16,22–43,45–54]. Owing to enthalpic (transannular interactions, bond and torsional strains) and entropic influences that hinder cyclization strategies, synthesis of seven-membered rings remains a great challenge [55–65]. Inspired by our previous work [66], our group develops a new kind of polysubstituted allenes as C₃ synthon to generate highly functionalized benzazepine derivatives by an unprecedented mode (Scheme 1, path f).

  Scheme 1

  

  Scheme 1.  Synthesis of benzazepine derivatives.

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  At the outset of our study, allene 1a and 4-methyl-N-(2-((phenylimino)methyl)phenyl)benzenesulfonamide 2a were selected for the initial reaction in the presence of 20 mol% DABCO (diazabicyclooctane) in CH₂Cl₂ at 25 ℃ (Table 1, entry 1). To our delight, the desired product could be obtained in 93% isolated yield. Then, other Lewis bases, such as Ph₃P, DBU (diazabicycloundecene) and Et₃N were also tested (entries 2–4). However, other Lewis bases were not suitable for this transformation. We further investigated a range of solvents, and EtOAc gave the best result for 3a (entries 5–12). Further examinations showed that the temperature is crucial for the formation of 3a (entries 13 and 14). Thus, we established the optimal reaction conditions for the construction of benzazepine derivatives as follows: use of 20 mol% DABCO as the catalyst and EtOAc as the solvent to perform the reaction at 25 ℃.

  Table 1

  

  Table 1.  Optimization of the reaction conditions.^a

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  Entry	Catalyst	Solvent	T (℃)	Yield (%)b
  1	DABCO	CH2Cl2	25	93
  2	PPh3	CH2Cl2	25	Trace
  3	DBU	CH2Cl2	25	0
  4	Et3N	CH2Cl2	25	0
  5	DABCO	THF	25	72
  6	DABCO	PhMe	25	68
  7	DABCO	EtOH	25	17
  8	DABCO	1, 4-Dioxane	25	70
  9	DABCO	MeCN	25	69
  10	DABCO	DMF	25	Trace
  11	DABCO	Et2O	25	37
  12	DABCO	EtOAc	25	99
  13	DABCO	EtOAc	0	74
  14	DABCO	EtOAc	60	81
  a Reactions were performed using 1a (0.23 mmol), 2a (0.1 mmol) and catalyst in 2 mL of the solvent at different temperatures for 20 h. b Isolated yields.

  With the optimized reaction conditions in hand, the generality and efficiency of different Schiff base derivatives were examined for this transformation (Scheme 2). With regard to 4-substituents of the R², both electron-withdrawing and electron-donating groups could obtain good yields (3b-3f). However, regarding 5-substituents of the R², electron-donating groups afforded products in higher yields than electron-withdrawing groups (3g-3j). Next, we examined substituents of R³. Both halogen and nitro substituents of the R³ gave good to excellent yields (3k-3n). Besides, different allenes were examined for this transformation. The results indicated that various substituted allenes were tolerated in this transformation with moderate to excellent yields (3o-3v).

  Scheme 2

  

  Scheme 2.  Synthesis of benzazepine derivatives. General conditions: 1 (0.23 mmol), 2 (0.1 mmol) and DABCO (0.02 mmol) were stirred in EtOAc (2.0 mL) at room temperature for 20 h. The isolated yields are shown.

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  To demonstrate the synthetic potential of this catalytic system, the scale-up preparation of 3a was investigated. The reaction of 4 mmol of the starting material (2a) proceeded smoothly, delivering the corresponding product 3a in 72% yield (Scheme 3a). Besides, the synthetic application of this methodology was demonstrated by the reaction of 3a and 3e (Scheme 3b). A Suzuki coupling reaction between 3e and phenylboronic acid proceeded smoothly in 70% yield. The amide group of 3a could be attacked by methylmagnesium bromide to get 4b and 4c in 40% and 33% yields. At last, we performed a preliminary investigation on the cytotoxicity of some selected products against HCT116 (human colorectal carcinoma cells) cancer cells (Scheme 3c). Several products exhibited some extent of cytotoxicity against HCT116 cancer cells, with IC₅₀ values of 37.98–68.05 µmol/L. These preliminary results indicate the potential applications of functionalized benzazepine derivatives in medicinal chemistry.

  Scheme 3

  

  Scheme 3.  Scale-up synthesis, further transformations and cytotoxicity of selected products. Positive control (chidamide) = 0.92 µmol/L.

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  To gain some insight into the mechanism, intermediate 3a' was captured in 13% yield in the presence of DABCO at room temperature (Scheme 4a). The structure of 3a' was confirmed by X-ray analysis (see Supporting information). Further, treatment of intermediate 3a' with DABCO allowed smooth formation of 3a in 99% yield (Scheme 4a). Moreover, we carried out deuterium labeling investigations (Scheme 4b). Deuterated products D-3a' and D-3a were obtained in 11% and 95% yields, respectively (see Supporting information for details). These results indicated that the possible carbanion intermediates were involved in the [3 + 4] cycloadditions.

  Scheme 4

  

  Scheme 4.  Mechanistic studies.

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  On the basis of the experimental results and previous reports [43], we developed plausible mechanisms for the [3 + 4] reaction (Scheme 5). Initially, allene 1a and the catalyst DABCO form zwitterionic intermediates (A↔A'). In path a, intermediate B-1 is formed from the intermediate A through proton transfer. It attacks the imine 2a to afford intermediate C-1 and then proton transfer leads to intermediate D-1. The subsequent cyclization and elimination of DABCO yield 3a'. In path b, intermediate A' deprotonates the benzenesulfonamido group in imine 2a to give the corresponding intermediate B-2. Subsequent Michael addition produces the intermediate C-2. Intermediate D-2 is formed from the intermediate C-2 through proton transfer. The cyclization of D-2 affords the intermediate E-2, which is followed by proton transfer and elimination of DABCO to produce 3a' and regenerate DABCO promoter. Finally, the product 3a is formed from 3a' through the eliminate of aniline and double-bond shift.

  Scheme 5

  

  Scheme 5.  Proposed mechanism.

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  In conclusion, we have developed a [3 + 4]-cycloaddition reaction of Schiff bases with α-substituted allenes which provides an efficient route to a series of biologically important benzazepine derivatives in good to excellent yields under mild conditions by an unprecedented mode and the proposed mechanism is supported by capturing the intermediate. Investigation on the cytotoxicity of selected products against HCT116 cancer cells indicates the potential applications of functionalized benzazepine derivatives in medicinal chemistry. The potential of this annulation with other electrophiles is currently being investigated in our laboratory.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Ke Wu: Writing – original draft, Data curation. Xiuqin Ruan: Methodology, Data curation. Shuolei Jia: Supervision. Enyuan Wang: Methodology. Qingfa Zhou: Writing – review & editing.

  Acknowledgment

  This work was financially supported by the National Natural Science Foundation of China (No. 21572271).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110646.

  
  
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• 

  Figure 1  Importance of benzazepines: Selected natural products and pharmaceutical agents.

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  Scheme 1  Synthesis of benzazepine derivatives.

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  Scheme 2  Synthesis of benzazepine derivatives. General conditions: 1 (0.23 mmol), 2 (0.1 mmol) and DABCO (0.02 mmol) were stirred in EtOAc (2.0 mL) at room temperature for 20 h. The isolated yields are shown.

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  Scheme 3  Scale-up synthesis, further transformations and cytotoxicity of selected products. Positive control (chidamide) = 0.92 µmol/L.

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  Scheme 4  Mechanistic studies.

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  Scheme 5  Proposed mechanism.

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  Table 1.  Optimization of the reaction conditions.^a

  Entry	Catalyst	Solvent	T (℃)	Yield (%)b
  1	DABCO	CH2Cl2	25	93
  2	PPh3	CH2Cl2	25	Trace
  3	DBU	CH2Cl2	25	0
  4	Et3N	CH2Cl2	25	0
  5	DABCO	THF	25	72
  6	DABCO	PhMe	25	68
  7	DABCO	EtOH	25	17
  8	DABCO	1, 4-Dioxane	25	70
  9	DABCO	MeCN	25	69
  10	DABCO	DMF	25	Trace
  11	DABCO	Et2O	25	37
  12	DABCO	EtOAc	25	99
  13	DABCO	EtOAc	0	74
  14	DABCO	EtOAc	60	81
  a Reactions were performed using 1a (0.23 mmol), 2a (0.1 mmol) and catalyst in 2 mL of the solvent at different temperatures for 20 h. b Isolated yields.

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•