A Theoretical and Experimental Perspective on the Stereochemistry of 1,3-Diazepan-2-ylidenes

Abstract

Diazepine compounds are well known for their broad range of biological activities and diverse applications. However, 1,3-diazepan-2-ylidenes remain unexplored in the literature. These compounds possess intriguing structural features that make them excellent candidates for studying rotational barriers associated with the resonance of the ketene moiety and the N1, N3 atoms, as well as electron-withdrawing substituents. NMR experiments conducted at room temperature suggest that the rotational barrier is sufficiently low to allow interconversion between conformers, or that the conformers are so similar that their signals cannot be resolved. Computational calculations were performed to estimate the rotational barrier, and additional NMR experiments were carried out at subambient temperatures in an attempt to separate the overlapping signals. All results support the hypothesis that the observed spectra arise from unresolved conformational overlap.

Key words
1,3-Diazepan-2-ylidenes; Synthesis; Stereochemistry; Theoretical calculations

INTRODUCTION

Diazepines constitute an important class of heterocyclic compounds due to their significant applications in the biological sciences. Benzodiazepines were the first heterocyclic compounds to be recognized as privileged structures (Evans et al. 1988, Welsch et al. 2010) and other 1,4-diazepine derivatives have demonstrated neuroprotective (Toti et al. 2022), antifungal (Ramirez et al. 2015), anticancer (Ramirez et al. 2015, Timaniya et al. 2023, Fahad et al. 2023), antimalarial (Insuasty et al. 2015), antitrypanosomal (Insuasty et al. 2015), and antileishmanial activities (Insuasty et al. 2015). Although 1,4-diazepine derivatives are better known for their pharmacological applications, 1,2-diazepines have also exhibited notable biological activities (Meanwell & Walker 2008, Meagher & Murugan 2008).

The 1,3-diazepine scaffold is similarly regarded as a privileged structure in medicinal chemistry (Malki et al. 2021). This moiety is present in numerous biologically active compounds, including natural products, and serves as a framework for the design of molecules with diverse biological activities, such as anticancer agents (e.g., pentostatin) (Woo et al. 1974, Agarwal et al. 1977), antibiotics (e.g., avibactam) (Bonnefoy 2004), and HIV protease inhibitors (e.g., DMP323) (Lam et al. 1996, Hodge et al. 1998) (Figure 1). Despite the extensive documentation on the synthesis of 1,3-diazepines, 1,3-diazepan-2-ylidenes remain virtually unexplored (Malki et al. 2022, Zhu et al. 2009).

Figure 1
Examples of drugs containing the 1,3-diazepine moiety.

Ketene dithioacetals are valuable building blocks in organic synthesis (Huang et al. 2020, Xu et al. 2019). These compounds readily undergo double vinylic substitution, enabling the one-step formation of heterocyclic compounds bearing exocyclic double bonds (Baliza et al. 2024, Sangi et al. 2014, 2019).

Recently, we employed these building blocks to synthesize new 1,3-diazepan-2-ylidenes and investigated their potential applications in materials science as nontoxic corrosion inhibitors (Figure 2). Although the diazepanes were successfully obtained, the 1H and 13C NMR spectra of compounds 6-10 are intriguing, raising questions regarding the stereochemistry of these structures (Souza et al. 2025).

Figure 2
Synthesis of 1,3-diazepines from ketene dithioacetals.

It is well known that the properties of compounds are strongly influenced by their rotational degrees of freedom and, consequently, by the stereochemical aspects of their structures (Sangi DP. 2016). In this study, we present both theoretical and experimental investigations of 1,3-diazepan-2-ylidenes, to better understand their stereochemistry properties.

MATERIALS AND METHODS

General information

Ketene dithioacetals (1–5) were prepared through a one-pot synthesis involving deprotonation, addiction to carbon disulfide and methylation as described by Baliza et al. (2024). Subsequently, 1,3-diazepines (6–10) were synthesized by double vinylic substitution, using putrecine as nucleophile to replace the methylsulfanyl groups in ketene dithioacetals, as reported by Souza et al. (2025).

Infrared spectra were recorded on a Bruker FT-IR Vertex 70 spectrophotometer in Attenuated Total Reflectance (ATR) mode. Additionally, mass spectrometry was conducted using a Shimadzu GCMS-QP2010 Plus instrument, and NMR analyses were performed on a Bruker Avance DRX 400 and a Varian VNMRS 500 MHz spectrometer.

Identification of 1,3-diazepines

The synthesized compounds (6-10) were identified using data from mass spectrometry, infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy, as detailed below. The hydrogen (¹H NMR) and carbon (¹³C NMR) spectra that are discussed in this work, are available as Supplementary Material (Figures S1-S20) for review and publication.

2-(nitromethylene)-1,3-diazepine (6): 1H NMR (500 MHz, DMSO) δ 8.83 (s, 2H), 6.39 (s, 1H), 3.71- 3.52 - (m, 4H), 1.71 – 1.65 (m, 4H); 13C NMR (126 MHz, DMSO-d₆) δ 162.81, 100.49, 44.62, 27.42. IR (ATR) (v_max/cm-1): 3292, 1594, 1353, 1189, 983, 763. MS (m/z, (%)): 157(58); 123(42); 70(63); 55(94); 44(100). Calcd for C₆H₁₂N₃O₂+ [M + H]+ = 158.0931, found 158.0954.

2-(1,3-diazepan-2-ylidene)malononitrile (7): 1H NMR (400 MHz, DMSO-d₆) δ 7.62 (s, 2H), 3.18 - 3.12 (m, 2H), 1.56 - 1.48 (m, 2H). 13C NMR (101 MHz, DMSO) δ 168.26, 119.06, 45.55, 33.89, 27.44. IR (ATR) (v_max/cm-1): 3288, 2221, 2173, 1573, 1363, 709. MS (m/z, (%)): 162(100); 133(37); 44(72). Calcd for C₈H₁₁N₄+ [M + H]+ = 163.0985, found 163.0982.

Methyl 2-cyano-2-(1,3-diazepan-2-ylidene)acetate (8): 1H NMR (400 MHz, DMSO-d₆) δ 8.10 - 7.87 (m, 2H), 3.57 (s, 3H), 3.31 – 3.25 (m, 4H), 1.67 – 1.56 (m, 4H). 13C NMR (101 MHz, DMSO) δ 168.94, 167.91, 119.55, 55.96, 50.43, 44.64, 26.93. IR (ATR) (v_max/cm-1): 3294, 2188, 1635, 1612, 1282, 1128, 671. MS (m/z, (%)): 195(100); 164(92); 112(40). HRMS (ESI): Calcd for C₉H₁₄N₃O₂+ [M + H]+ = 196.1079, found 196.1089.

Diethyl 2-(1,3-diazepan-2-ylidene)malonate (9): 1H NMR (400 MHz, MeOD) δ 4.09 (q, J = 7.1 Hz, 4H), 3.26 - 3.21 (m, 4 H), 1.72 – 1.65 (m, 4H), 1.25 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, MeOD) δ 171.22, 170.54, 76.64, 59.08, 45.14, 27.70, 13.37. IR (ATR) (v_max/cm-1): 3289, 1606, 1141, 1070, 792. HRMS (ESI): Calcd for C₁₂H₂₁N₂O₄+ [M + H]+ = 257.1502, found 257.1510.

2-(1,3-diazepan-2-ylidene)-3-oxo-3-phenylpropanenitrile (10): 1H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 7.80 – 7.70 (m, 2H), 7.50 – 7.38 (m, 3H), 5.86 (s, 1H), 3.45 (s, 4H), 1.86 (s, 4H). 13C NMR (101 MHz, CDCl₃) δ 190.45, 168.80, 140.13, 130.69, 127.99, 127.72, 122.27, 70.91, 45.31, 27.32. IR (ATR) (v_max/cm-1): 3278, 2187, 1599, 1347, 702. MS (m/z, (%)): 241(100); 240(69); 105(42); 77(70). Calcd for C₁₄H₁₆N₃O+ [M + H]+ = 242.1291, found 242.1233.

Computational Methods

The C=C rotational barriers in compounds 6–10 (Figure 1) were explored by scanning the N-C=C-X dihedral angle in 12 increments of 15°, starting from the most stable twist-chair conformation of cycloheptane (Bocian et al. 1975) for the 1,3-diazepane ring. Calculations were performed at the B3LYP-GD3BJ/6-311++G(d,p) (Becke 1988, Lee et al. 1988, Grimme et al. 2011, Ditchfield et al. 1971) level of theory for the gas phase using an unrestricted approach within the Gaussian 16 software suite (Frisch et al. 2016), as the transition state corresponds to a diradical. To ensure adequate sampling of the conformational space of the 1,3-diazepane ring, an initial conformational search was performed using the Global Optimization Algorithm for conformer exploration (GOAT) at the GFN2-xTB level (Bannwarth et al. 2019), as implemented in the ORCA program. The lowest-energy structures obtained correspond to the starting geometries used in the scan calculations. A total of 3 conformers were identified for compound 6, 4 for compound 7, 6 for compound 8, 37 for compound 9, and 6 for compound 10; however, the geometry of the seven-membered ring remained essentially unchanged across the conformers. Potential energy surfaces were subsequently generated at the same GFN2-xTB level of theory including implicit solvation in DMSO, methanol, or chloroform using the ALPB model. The energy minima identified on each gas-phase potential energy surface were subsequently optimized, and NMR chemical shifts relative to tetramethylsilane were computed using the GIAO (Gauge-Independent Atomic Orbital) method (Wolinski et al. 1990) at the same DFT level of theory.

RESULTS AND DISCUSSION

The analysis of nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry (both low and high resolution) supports the proposed structure of the 1,3-diazepine ylidenes (Figure 3). However, the presence of unresolved signals in the NMR spectra is intriguing and warrants further investigation.

Figure 3
Structure of 1,3-diazepine-2-ylidene derivatives (6-10).

Analysis of the ¹H NMR spectra revealed that derivatives 6–10 did not exhibit singlets in the 2.5–2.8 ppm range, which are characteristic of methylsulfanyl groups in ketene dithioacetals (1–5). As expected, compounds 6–10 showed signals in the 3.1–3.7 ppm range, corresponding to 4H integrated CH₂ groups bonded to N-H, along with signals in the 1.4–1.7 ppm range, also integrated to 4H, representing methylene groups at positions 5 and 6, completing the diazepine ring.

Beyond the signals corresponding to the substituents groups, the 13C NMR spectra of compounds 6–10 presented signals at 27 and 45 ppm, assigned to C5/C6 and C4/C7, respectively. The mesomeric effect of the nitrogen lone pair and the resonance of the exocyclic double bond with electron-withdrawing substituents deshielded C2 and shielded C8, resulting in C8 appearing in the range of 34–100 ppm and C2 in the range of 162–170 ppm.

In order to clarify the structural assignment and obtain information of equivalence of C4/C7 and C5/C6 more, we performed bidimensional experiments to compound 6. The COSY NMR (Figure S18) demonstrated that signal corresponding to H5 and H6 (1.68 ppm) are correlating with H4 and H7 (3.56 ppm), in addition to that, NOESY (Figure S19) showed correlation between H1 and H3 (8.83 ppm) and H4 and H7, reinforcing the structural characterization.

The DEPT experiment (Figure S4) showed that C4/C7 and also C5/C6 are methylenes, and even their intensity compared with the other signals are an important indication that each signal on 27 and 44 ppm correspond to two carbons on the structure. Completing the structural assignment, HMBC (Figure S20) to the compound 6 shows correlation between H5 and H6 with C4 and C7, and also between H4 and H7 with C5 and C6, in the cases separated by two bonds.

Interestingly, only one signal was observed for carbons 4 and 7, and another for carbons 5 and 6 in the ¹³C NMR spectra of compounds 6, 8, and 10. These results suggest two possibilities:

• 1) The exocyclic bond exhibits pseudo-double-bond character with rapid rotation.

• 2) Carbons 4 and 7, as well as 5 and 6, are in such close proximity that their signals are unresolved.

To clarify this observation, theoretical and experimental studies were conducted. The potential energy surfaces of compounds 6–10 (Figure 4) revealed a single energy minimum for each compound, except for compound 10, which also displayed a high-energy conformer (>10 kcal mol⁻¹ above the global minimum) at an N-C-C-X dihedral angle of 60°. Most compounds exhibited rotational barriers exceeding 20 kcal mol⁻¹, in the order 6 > 7 > 8 > 10 > 9, with compound 9 having a relatively lower barrier of approximately 16 kcal mol⁻¹. These results resemble the behavior of the compounds in the solvents where the experiments were performed, as illustrated in the Supplementary Material (Figure S21).

Figure 4
Potential energy surfaces of compounds 6-10 upon rotation of the N-C-C-X dihedral angle.

The single ¹³C NMR signal for CH₂(NH) observed in unsymmetrical compounds like 6, 8, and 10 may suggest rapid pseudo-double-bond rotation, facilitated by the mesomeric effect of the nitrogen lone pair of electrons. This resonance effect is further corroborated by the planar structure of the nitrogen-based moiety in the optimized conformers (Figure 5). However, these rotational barriers are higher than observed in amides, which typically display two NMR signals for H(N) hydrogens (in primary amides) or Me(N) carbons (in tertiary amides) at room temperature (Clayden et al., 2001). Thus, the coincident ¹³C signals appear to be due to chemical equivalence rather than dynamic averaging. However, it is interesting that the signals are well resolute, with line widths between 6 - 10 Hz (0.06 - 0.10 ppm).

Figure 5
Optimized conformers of compounds 6–10, illustrating the planar geometry of the endocyclic nitrogens, which results from resonance with the adjacent C=C pseudo-double bond.

To determine whether the identical C-13 chemical shifts for both CH₂(NH) groups are a result of the rapid rotation of the C=C pseudo-double bond or merely due to similar chemical environments, NMR chemical shifts were calculated for the optimized geometries of compounds 6–10 in gas phase (Table I). Because the analysis is based on the relative difference between two 13C signals within the same molecule, solvent effects are expected to influence both nuclei similarly; thus, the qualitative interpretation is not expected to change significantly between gas-phase and solution-phase calculations. The computed chemical shifts for CH₂(NH) are very similar, even in the unsymmetrical compounds 6, 8, and 10, with differences ranging from 0.3 to 2.3 ppm. To verify if these small differences in chemical shifts could become detectable when the rotation slows, low-temperature NMR experiments were required.

Table I
Calculated C-13 chemical shifts for compounds 6–10 relative to TMS (in ppm).

Compound	CH2(NH)	CH2(NH)’
6	46.33	46.74
7	45.59	45.26
8	45.36	46.66
9	44.64	46.90
10	45.68	46.24

The NMR spectra remain unchanged, even when recorded at temperatures as low as -40 °C, the signals are well resolute, with line widths between 6 - 10 Hz (0.06 - 0.10 ppm), while the smallest calculated difference for the signals was 33 Hz. These findings, together with the computed rotational barriers, provide strong evidence that 1,3-diazepines 6–10 do not exhibit fast rotation of the exocyclic double bond.

CONCLUSIONS

Diazepine derivatives are an important class of heterocyclic compounds with a wide range of biological activities. Five 1,3-diazepan-2-ylidenes were synthesized by vinylic substitution and identified using nuclear magnetic resonance presenting only one chemical shift to carbon on CH₂NH group, suggesting pseudo-double-bond character to exocyclic bond or unresolved signals.

Theoretical studies revealed a planar structure for the nitrogen-based moiety in the optimized conformers and indicated rotational barriers close to 20 kcal mol⁻¹, which do not suggest rapid pseudo-double-bond rotation.

NMR chemical shifts were calculated for the optimized geometries of compounds 6–10 and the computed chemical shifts for CH₂(NH) were found to be very similar, even in the unsymmetrical compounds 6, 8, and 10, with differences ranging from 0.3 to 2.3 ppm. Low-temperature NMR experiments were conducted, showing that the NMR signals remain unresolved. This observation rules out the possibility of rapid pseudo-double-bond rotation and supports the hypothesis that carbons 4 and 7, as well as carbons 5 and 6, are in such close proximity that their signals overlap.

SUPPLEMENTARY MATERIAL

Figure S1-S21.

Acknowledgements

The authors acknowledge the UFF and UFLA for their support. The authors declare that no funding was obtained for the research and publication of this article.

Data availability

The data that support the findings of this study are available in the supplementary material of this article.

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Correspondence

Correspondence to: Diego Pereira Sangi [e-mail]

Handling editor

Jamal Rafique

Publication Dates

• Publication in this collection
  23 Oct 2026
• Date of issue
  2026

History

• Received
  6 Jan 2026
• Accepted
  23 Apr 2026