Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

Abstract

Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and microwave irradiating conditions in ethanol solvent. The structures of the isolated products were fully characterized by spectral and analytical data as well as X-ray single crystal of selected examples.

1. Introduction

The azabicyclo[3.3.1]nonane moiety is a privileged scaffold embedded in the structures of numerous bioactive natural products (Figure 1) [1,2]. The azabicyclo[3.3.1]nonane derivatives are reported to have diverse biological applications. For example, 1-azabicyclo[3.3.1]nonanes are useful for the treatment of psychotic and neurodegenerative disorders [3,4]. The 2-azabicyclo[3.3.1]nonane skeleton is present in several important narcotic analgesics and marine alkaloids [5,6,7]. 3-Azabicylo[3.3.1]nonane is the core substructure of the marine natural product; Haliclonin A (Figure 1) [8,9]. 9-Azabicyclo[3.3.1]nonane derivatives possess cytotoxic [10], dopamine D3 receptor ligands [11], high sigma-2 receptor affinities [12], and are used for the treatment of diabetes mellitus [13]. Furthermore, 1,4-diazabicyclo[3.3.1]nonane derivatives are reported to exhibit high in vivo affinity and selectivity for the dopamine transporter (DAT) blockers [14,15]. 3,7-Diazabicyclo[3.3.1]nonanes are reported to be useful in the treatment of cardiac arrhythmias [16], and exhibited anti-platelet, antithrombotic activities [17], as well as high affinities at various nicotinic acetylcholine receptors (nAChRs) [18,19,20]. 3,9-Diazabicyclo[3.3.1]nonanes showed the 5-HT3 receptor antagonist [21] and opioid δ and μ-receptor activities [22,23]. Triazabicyclo[3.3.1]nonane derivatives such as 2,6,9- and 3,7,9-triazabicyclo[3.3.1]nonanes [24,25,26,27,28] were synthesized from dimerization of α,β-unsaturated carbonyl compounds with alkylamines. Some 1,3,5,7-tetraazabicyclo[3.3.1]nonane derivatives have antithrombotic activities [29]. Although tremendous progress has been achieved in the synthesis of mono-, di-, and tri-azabicyclo[3.3.1]nonanes [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27], the synthesis of tetra- and penta-azabicyclo[3.3.1]nonane frameworks has rarely been disclosed in the literature [30,31,32,33].

The microwave irradiation methodology is widely employed in organic reactions because it has several advantages over conventional heating, resulting in high yields, low by-products, rapid heating and easy purification [34,35,36,37,38,39,40,41]. Mechanistically, microwave irradiation affects the reaction through internal heating by direct coupling of microwave energy with the bulk reaction mixture. Furthermore, the eco-friendly ultrasound platform has receiving much interest due to its high impacts on organic synthesis, medicinal chemistry and materials science [42,43,44,45,46]. It leads to the formation of pure products in high yields and selectivity in a shorter reaction time. In continuation of our research work employing ultrasound and microwave irradiations in the synthesis of biologically active heterocycles [47,48,49,50,51,52,53,54,55,56,57], we envisaged herein an efficient and versatile one-pot protocol for rapid assembly of novel C₂-symmetric 2,3,6,7,9-pentaazabicyclo[3.3.1]nonane derivatives through dimerization of 3-oxo-2-arylhydrazonopropanals with ammonium acetate via a double Mannich-type reaction under three different heating platforms: conventional, ultrasound and microwave irradiation. The structures of the obtained products are established from their single crystal X-ray analysis and spectral data (IR, MS, HRMS, ¹H- and ¹³C-NMR).

2. Results

The intermolecular Mannich reaction is considered to be a powerful route for the synthesis of azacyclic products from acyclic substrates [58]. At first, the investigations focused on screening various reaction parameters (e.g., solvents, bases and heating techniques) for optimizing the reaction conditions of the double-Mannish reaction of the 3-oxo-2-arylhydrazonopropanal derivative 1a with ammonium acetate were thoroughly evaluated and the reaction was followed by TLC till almost full conversion of the starting substrates and the results are depicted in Table 1. Heating the 3-oxopropanal derivative 1a with double equivalents of ammonium acetate in ethanol under either reflux temperature (15 h), ultrasound irradiation (US) (120 min at 80 °C and 110 W), or microwave irradiation (MW) (30 min at 80 °C and 200 W) in the absence of catalysts, only a trace amount of product was detected by TLC (run 1, Table 1). When the reaction was heated at reflux using triethylamine (Et₃N) as catalyst (15 mol%) for 4 h (as examined by TLC), it led to the formation of the 2,3,6,7,9-pentaazabicyclo[3.3.1]nonane derivative 2a in 70% isolated yield (run 2, Table 1). The structure of reaction product 2a was confirmed from its spectral data (IR, MS, HRMS, ¹H- and ¹³C-NMR). ¹H-NMR spectrum of compound 2a showed triplet at δ 4.30 (D₂O-exchangeable) assigned to the NH proton and a doublet at δ 6.76 due to the symmetric-bridgehead H1 and H5-protons in addition to a multiplet at δ 7.3–7.95, corresponding to 16 aromatic protons. ¹³C-NMR spectrum of 2a exhibited symmetric 11 signals at δ 56.48, 118.94, 127.70, 127.98, 128.92, 129.99, 132.15, 136.98, 138.37, 141.88 and 189.39, corresponding to 30 aromatic and aliphatic carbons. When the same reaction was repeated under US (for 60 min) and MW (for 5 min), the product 2a was obtained in 82% and 87% yields, respectively (run 2, Table 1). For the same reaction, use of 25 mol% of Et₃N resulted in a significant increase in the product yield, to 78%, 89% and 94% when the reaction was carried out at reflux (3 h), US (50 min) and MW (3 min), respectively (run 3, Table 1). Further increase in the amount of Et₃N (30 mol%) could not significantly improve the yield, as shown in run 4, Table 1. Further evaluation of the effect of the molar ratio of 1a and ammonium acetate in the presence of 25 mol% of Et₃N was attempted, where product 2a was formed in 66%, 73% and 80% yields after heating at reflux (3 h), US (50 min) and MW (3 min), respectively, when 1a and ammonium acetate (1:1 molar ratio) were employed (run 5, Table 1). Repeating the reaction of 1a and ammonium acetate (2:1 molar ratio) gave 60%, 68% and 73% yields of 2a upon heating at reflux (3 h), US (50 min) and MW (3 min), respectively (run 6, Table 1). Using methanol or isopropanol solvents instead of ethanol in the presence of Et₃N (25 mol%) and 1:2 molar ratio of 1a and ammonium acetate had little effect on the product yields under all heating modes, as shown in runs 7 and 8, Table 1. Non-alcoholic solvents lowered the reaction yields and increased the reaction time, where employing n-hexane, acetic acid, dimethylformamide (DMF) or toluene as reaction solvents resulted in the formation of 2a in 30~35%, 40~52% and 50~65% yields, under reflux, US and MW conditions, respectively, as shown in runs 9–12, Table 1. Keeping ethanol as solvent, further attempts to evaluate the effect of base-types (pyridine, DABCO, DBU, NaHCO_3, K₂CO_3, NaOH) on the reaction yields were studied and in all cases, regardless of whether an organic or inorganic base catalyst was employed (25 mol%), the overall yields decreased sharply; 10~20%, 10~28% and 15~35% yields, under the applied activation modes—thermal, US and MW—respectively (runs 13–18, Table 1). From the obtained data in Table 1, it can be concluded that EtOH/Et₃N is the most effective reaction condition for achieving the stated goals.

Next, a variety of C₂-symmetric tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene derivatives were prepared in accordance with the above optimized reaction conditions. The use of several 3-oxo-2-arylhydrazonopropanal derivatives 1a–p with ammonium acetate afforded the corresponding double Mannich-type products 2a–p in good to excellent isolated yields and the reactions were followed by TLC until full conversion of the starting substrates (Table 2). It was gratifying to see that the reaction proceeds well, with high isolated yields (81~94%) for all derivatives under microwave irradiation within 3~9 min at 80 °C (200 W). Reaction yields were slightly decreased by conducting the reaction under ultrasound at 80 °C (110 W), with the products being obtained in 73~89% isolated yields. When reactions were carried out under conventional heating mode, the isolated yields varied from 62 to 86% after 3~8 hours when followed by TLC. All the resulted products were established based on their elemental analyses and spectral data (IR, MS, HRMS, ¹H- and ¹³C-NMR), as well as single crystal X-ray crystallography, of three examples, 2f, 2k and 2p, as shown in Figure 2a–c [59]. It is worth mentioning that the bicyclic scaffolds adopt a unique C₂-symmetric V-shaped structures [60].

A plausible mechanism is proposed, as outlined in Scheme 1, on the basis of the aforementioned results for the tandem formation of the 2,3,6,7,9-pentaazabicyclo[3.3.1]nonane derivatives 2a–p through a Mannich-type reaction. At first, ammonium acetate is dissociated into ammonia and acetic acid. Then, nucleophilic addition of ammonia to the aldehydic carbonyl of compound 1, followed by dehydration through the intermediary A~C furnished the iminium ion intermediate D. A second molecule of structure 1 is deprotonated by Et₃N as basic catalyst to form the arylazo-enolate ion intermediate E. The resonated intermediate F attacks the iminium ion intermediate D to form the non-isolated Mannich adduct G that cyclizes to form the triazacyclic intermediate H by intramolecular attacking of the amine function to the aldehyde function. Finally, loss of water molecule from H produced the pentaazabicyclo[3.3.1]nonane system 2.

3. Materials and Methods

3.1. General Information

Melting points were recorded on a Griffin melting point apparatus and are reported uncorrected. IR spectra were recorded using KBr disks using a Perkin-Elmer System 2000 FT-IR spectrophotometer (Perkin Elmer, Shelton, CT, USA). ¹H-NMR (600 MHz) and ¹³C-NMR (150 MHz) spectra were recorded at 25 °C using DMSO-d₆ as solvent with TMS as internal standard on a Bruker DPX 600 super-conducting NMR spectrometer (Bruker, Karlsruhe, Germany). Chemical shifts δ are reported in ppm. Low-resolution electron impact mass spectra [MS (EI)] and high-resolution electron impact mass spectra [HRMS (EI)] were performed using a high-resolution GC-MS (DFS) thermo spectrometer at 70.1 eV using a magnetic sector mass analyzer (Thermo, Bremen, Germany). Follow-up of the reactions and checking homogeneity of the prepared compounds was carried out by using thin layer chromatography (TLC). Microwave experiments were carried out using a CEM Discover Labmate microwave apparatus (300 W with CHEMDRIVER software; Matthews, NC, USA). Reactions were conducted under microwave irradiation in heavy-walled Pyrextubes fitted with PCS caps (closed vessel under pressure). The X-ray crystal structures were determined by using a Rigaku R-AXISRAPID diffractometer (Rigaku, Tokyo, Japan) and Bruker X8 Prospector and the collection of single crystal data was made at room temperature by using Cu-Kα radiation. The data were collected at room temperature. The structures were solved by using direct methods and expanded using Fourier techniques. The non-hydrogen atoms were refined anisotropically. The structures were solved and refined using the Bruker SHELXTLSoftware Package (Structure solution program-SHELXS-97 and Refinement program-SHELXL97) [61].

Data were corrected for the absorption effects using the multi-scan method (SADABS). Sonication was performed in MKC6, Guyson ultrasonic bath (Model-MKC6, operating frequency 38 kHz ± 10% and an output power of 110 Watts) with a digital timer (6 s to 100 min) and a heater, allowing solution heating to be set from 20 to 80 °C in 1 °C increments. The inside tank dimensions are 150 × 300 × 150 mm (length × width × depth) with a fluid capacity of 6 L. The 3-oxo-2-arylhydrazonopropanal derivatives 1a–p were prepared following reported procedures in the literature [62].

3.2. Synthesis of 2,3,6,7,9-Pentaazabicyclo[3.3.1]nona-3,7-diene Derivatives 2a–p

3.2.1. General Method A

A mixture of the appropriate arylhydrazonopropanals 1a–p (5 mmol) and ammonium acetate (10 mmol) was dissolved in of ethanol (7 mL), then triethylamine (25 mol%) was added and the reaction mixture was refluxed for 3–8 h (monitored by TLC using a mixture of petroleum ether (bp 60–80):EtOAc (2:1)). The reaction mixture was then evaporated under reduced pressure and the solid product, so formed, was recrystallized from EtOH/DMF to give the corresponding 2,3,6,7,9-pentaazabicyclo[3.3.1]nonane products 2a–p.

3.2.2. General Method B

In a round-bottomed three-necked flask, a mixture of the appropriate arylhydrazonopropanals 1a–p (5 mmol) and ammonium acetate (10 mmol) in of ethanol (7 mL), then triethylamine (25 mol%) was added and the reaction mixture was sonicated in a MKC6, Guyson ultrasonic bath (Model-MKC6, operating frequency 38 kHz ± 10% and an output power of 110 W) for 50–110 min at 80 °C. The reaction was controlled by TLC and continued until the starting substrates were completely consumed, then left to cool to room temperature. In each case, the solid product, so formed, was collected by filtration, washed with ethanol, dried and recrystallized from EtOH/DMF to give the corresponding products 2a–p.

3.2.3. General Method C

In a process glass vial, a mixture of the appropriate arylhydrazonopropanals 1a–p (5 mmol) and ammonium acetate (10 mmol) in ethanol (7 mL), then triethylamine (25 mol%) was added. The vial was capped properly, and thereafter, the mixture was heated under microwave irradiating conditions at 80 °C and 300 W for the appropriate reaction time as listed in Table 2. After cooling to room temperature, the products were isolated by filtration, washed with ethanol, dried and recrystallized from EtOH/DMF to give the corresponding products 2a–p, see Supplementary materials.

2,6-Di(4-chlorophenyl)-4,8-di(4-fluorobenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2a): Pale yellow color; m.p. 245–246 °C; IR (KBr): 3331, 3073, 1636, 1597 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.30 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.31 (t, 4H, J = 9 Hz), 7.45 (d, 4H, J = 9.6 Hz), 7.65 (d, 4H, J = 9 Hz), 7.93–7.95 (m, 4H); ¹³C-NMR (DMSO-d₆): δ = 56.93, 115.45, 115.60, 119.49, 128.25, 129.44, 133.39, 133.45, 133.92, 138.74, 142.35, 164.03, 165.69, 188.35; MS (EI, 70 eV): m/z (%) = 588.90 (M⁺, 6), 463.0 (34), 314.0 (18), 138.0 (5), 123.0 (100), 95 (29); HRMS (EI): m/z calcd for C₃₀H₁₉Cl₂F₂N₅O₂: 589.0884; found: 589.0878.

2,6-Di(4-bromophenyl)-4,8-di(4-fluorobenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2b): Yellow color; m.p. 216–217 °C; IR (KBr): 3332, 3065, 1633, 1597 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.30 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.29–7.33 (m, 4H), 7.56–7.60 (m, 8H), 7.92–7.95 (m, 4H); ¹³C-NMR (DMSO-d₆): δ = 56.37, 114.97, 115.12, 115.83, 119.36, 131.84, 132.91, 132.97, 133.39, 133.41, 138.28, 142.26, 163.55, 165.21, 187.84; MS (EI, 70 eV): m/z (%) = 678.80 (M⁺, 5), 508.9 (19), 498.8 (3), 359.9 (10), 181.9 (3), 154.9 (8), 123.0 (100), 95.0 (27); HRMS (EI): m/z calcd for C₃₀H₁₉Br₂F₂N₅O₂: 676.9874; found: 676.9865.

4,8-Di(benzoyl)-2,6-di(4-chlorophenyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2c): Pale yellow color; m.p. 223–224 °C; IR (KBr): 3323, 3066, 1648, 1600 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.31 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.44 (d, 4H, J = 1.8 Hz), 7.49 (t, 4H, J = 7.8 Hz), 7.59 (t, 2H, J = 7.5 Hz), 7.63–7.65 (m, 4H), 7.83 (d, 4H, J = 7.2 Hz); ¹³C-NMR (DMSO-d₆): δ = 56.48, 118.94, 127.70, 127.98, 128.92, 129.99, 132.15, 136.98, 138.37, 141.88, 189.39; MS (EI, 70 eV): m/z (%) = 553.30 (M⁺, 15.9), 448.2 (4), 427.2 (70), 138.1 (5), 127.0 (10), 105.1 (100), 77.0 (33); HRMS (EI): m/z calcd for C₃₀H₂₁Cl₂N₅O₂: 553.1072; found: 553.1067.

4,8-Di(benzoyl)-2,6-di(4-bromophenyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2d): Pale yellow color; m.p. 245–247 °C; IR (KBr): 3334, 2919, 1634, 1593 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.34 (t, 1H, J = 2.4 Hz, NH), 6.78 (s, 2H, H-1, H-5), 7.48 (t, 4H, J = 7.8 Hz), 7.55–7.60 (m, 10H), 7.83 (t, 4H, J = 7.8 Hz); ¹³C-NMR (DMSO-d₆): δ = 56.43, 115.79, 119.31, 127.99, 130.01, 131.81, 132.17, 136.96, 138.41, 142.28, 189.38; MS (EI, 70 eV): m/z (%) = 643.1 (M⁺+2, 27), 538.1 (6), 471.1 (97), 354.1 (4), 340.1 (36), 171.0 (10), 105.0 (100), 77 (17); HRMS (EI): m/z calcd for C₃₀H₂₁Br₂N₅O₂: 641.0062; found: 641.0048.

4,8-Di(benzoyl)-2,6-di(2-nitrophenyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2e): Pale yellow color; m.p. 233–234 °C; IR (KBr): 3302, 3063, 1664, 1577 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.52 (t, 1H, J = 2.4 Hz, NH), 6.71 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.38 (t, 4H, J = 7.5 Hz), 7.44 (t, 2H, J = 7.8 Hz), 7.50 (t, 2H, J = 7.8 Hz), 7.50 (d, 4H, J = 7.2 Hz), 7.80–7.86 (m, 4H), 8.00 (d, 2H, J = 7.8 Hz); ¹³C-NMR (DMSO-d₆): δ = 58.65, 125.62, 125.74, 126.77, 127.92, 128.93, 131.57, 133.89, 136.93, 137.71, 139.64, 143.16, 189.91; MS (EI, 70 eV): m/z (%) = 575.20 (M⁺, 70), 558.2 (48), 527.2 (5), 438.2 (35), 410.2 (10), 305.1 (12), 214.1 (16), 105.0 (100), 77.0 (35); HRMS (EI): m/z calcd for C₃₀H₂₁N₇O₆: 575.1553; found: 575.1549.

4,8-Di(4-chlorobenzoyl)-2,6-diphenyl-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2f): Yellow color; m.p. 215–216 °C; IR (KBr): 3337, 3029, 1632, 1589 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.25 (t, 1H, J = 2.4 Hz, NH), 6.77 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.11 (t, 2H, J = 7.5 Hz), 7.38–7.41 (m, 3H), 7.54–7.57 (m, 3H), 7.64–7.66 (m, 3H), 7.86–7.88 (m, 3H); ¹³C-NMR (DMSO-d₆): δ = 56.46, 117.44, 123.85, 128.04, 129.10, 131.89, 135.80, 136.86, 137.77, 142.98, 188.04; MS (EI, 70 eV): m/z (%) = 553.10 (M⁺, 10), 461.0 (36), 414.1 (7), 387.1 (5), 321.0 (4), 296.1 (42), 139.0 (100), 111.0 (23), 77.0 (22); HRMS (EI): m/z calcd for C₃₀H₂₁Cl₂N₅O₂: 553.1072; found: 553.1068.; Crystal Data, C₃₀H₂₁Cl₂N₅O₂, M = 554.42, triclinic, crystal size = 0.140 × 0.260 × 0.370 mm, a = 6.3807(7) Å, b = 12.9107(13) Å, c = 16.2532(17) Å, α = 94.517(5)°, β = 97.765(5)°, γ = 99.214(5)°, V = 1302.6(2) ų, T = 296(2) K, space group: P -1, Z = 2, calculated density = 1.414 g/cm³, no. of reflection measured 20549, θ _max = 66.87°, R1 = 0.0557 (CCDC 1885322) [59].

2,6-Di(4-bromophenyl)-4,8-di(4-chlorobenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2g): Orange color; m.p. 261–262 °C; IR (KBr): 3344, 2980, 1635, 1587 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.30 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 3 Hz, H-1 and H-5), 7.55 (dd, 4H, J =1.8 Hz, J = 1.8 Hz), 7.59 (s, 8H), 7.86 (dd, 4H, J = 1.8 Hz, J=1.8 Hz); ¹³C-NMR (DMSO-d₆): δ = 56.42, 115.97, 119.43, 128.09, 131.84, 131.96, 135.57, 138.16, 142.22, 188.04; MS (EI, 70 eV): m/z (%) = 710.9 (M⁺+2, 4), 540.9 (25), 514.9 (7), 480.9 (3), 437.0 (5), 375.9 (15), 154.9 (15), 139.0 (100), 111.0 (40), 90.0 (5), 75.0 (15); HRMS (EI): m/z calcd for C₃₀H₁₉Br₂Cl₂N₅O₂: 708.9283; found: 708.9279.

2,6-Di(4-chlorophenyl)-4,8-di(4-bromobenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2h): Pale yallow color; m.p. 255–256 °C; IR (KBr): 3350, 3090, 1634, 1585 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.33 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.47 (d, 4H, J = 9 Hz), 7.66 (d, 4H, J = 9 Hz), 7.70 (d, 4H, J = 8.4 Hz), 7.80 (d, 4H, J = 8.4 Hz); ¹³C-NMR (DMSO-d₆): δ = 56.50, 119.11, 126.13, 127.88, 128.97, 131.05, 132.09, 135.95, 138.09, 141.83, 188.22; MS (EI, 70 eV): m/z (%) = 710.7 (M⁺+2, 6), 584.8 (47), 556.8 (3), 387.9 (7), 375.9 (22), 182.9 (100), 154.9 (36), 127.0 (33), 111.0 (26), 75.0 (15); HRMS (EI): m/z calcd for C₃₀H₁₉Br₂Cl₂N₅O₂: 708.92825; found: 708.9278.

4,8-Di(4-bromobenzoyl)-2,6-di(4-bromophenyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2i): Yellow color; m.p. 264–265 °C; IR (KBr): 3346, 2990, 1638, 1592 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.31 (t, 1H, J = 2.7 Hz, NH), 6.73 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.58–7.64 (m, 8H), 7.68 (d, 4H, J = 9 Hz), 7.80 (d, 4H, J = 8.4 Hz); ¹³C-NMR (DMSO-d₆): δ = 56.43, 115.97, 119.46, 126.15, 131.04, 131.85, 132.10, 135.92, 138.12, 142.22, 188.19; MS (EI, 70 eV): m/z (%) = 800.7 (M⁺+4, 2), 630.8 (18), 587.8 (6), 560.8 (12), 480.9 (16), 419.9 (8), 208.9 (12), 182.9 (100), 154.9 (80), 90.0 (12), 76.0 (46); HRMS (EI): m/z calcd for C₃₀H₁₉Br₄N₅O₂: 796.8272; found: 796.8268.

4,8-Di(4-methoxybenzoyl)-2,6-diphenyl-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2j): Pale yellow color; m.p. 237–238 °C; IR (KBr): 3328, 2974, 1626, 1596 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 3.82 (s, 6H, 2OCH₃), 4.24 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 2.4 Hz, H-1, H-5), 7.03 (dd, 4H, J = 1.8 Hz, J = 1.8 Hz), 7.08 (t, 2H, J = 7.2 Hz), 7.37–7.39 (m, 4H, ArH), 7.64 (d, 4H, J = 8.4 Hz), 7.87–7.91 (m, 4H); ¹³C-NMR (DMSO-d₆): δ = 55.41, 56.43, 113.38, 117.10, 123.42, 129.13, 129.45, 132.40, 138.53, 143.13, 162.57, 187.74; MS (EI, 70 eV): m/z (%) = 545.0 (M⁺, 11), 453.0 (25), 383.0 (3), 292.0 (22), 135.0 (100), 107.0 (5), 92.0 (12), 77.0 (20); HRMS (EI): m/z calcd for C₃₂H₂₇N₅O₄: 545.2063; found: 545.2058.

2,6-Di(4-chlorophenyl)-4,8-di(4-methoxybenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2k): Yellow color; m.p. 247–249 °C; IR (KBr): 3319, 3007, 1597, 1566 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 3.81 (s, 6H, 2CH₃O), 4.30 (t, 1H, J = 2.4 Hz, NH), 6.76 (d, 2H, J = 2.4 Hz, H-1, H-5), 7.03 (d, 4H, J = 9 Hz), 7.45 (d, 4H, J = 9 Hz), 7.66 (d, 4H, J = 9 Hz), 7.91 (d, 4H, J = 9 Hz); ¹³C-NMR (DMSO-d₆): δ = 55.40, 56.03, 56.43, 113.18, 113.42, 118.48, 118.71, 118.92, 127.42, 128.96, 132.46, 138.83, 141.97, 162.41, 162.64, 162.84, 187.69; MS (EI, 70 eV): m/z (%) = 613.10 (M⁺, 7), 487.1 (25), 450.1 (3), 421.1 (5), 326.1 (10), 161.0 (3), 135.0 (100), 77.0 (10); HRMS (EI): m/z calcd for C₃₂H₂₅Cl₂N₅O₄: 613.1284; found 613.1278. Crystal Data: C₃₂H₂₅Cl₂N₅O₄, M = 614.49, monoclinic, crystal size = 0.200 × 0.120 × 0.020 mm, a = 25.381(2) Å, b = 7.6990(3) Å, c = 25.477(2) Å, α = 90°, β = 145.50(1)°, γ = 90°, V = 2819.7(8) ų, T = -123.0 °C, space group: P21/c, Z = 4, calculated density = 1.447 g/cm³, no. of reflection measured 15678, θ _max = 50.1°, R1 = 0.0403 (CCDC 1885339) [59].

2,6-Di(4-bromophenyl)-4,8-di(4-methoxybenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2l): Pale yellow color; m.p. 255–256 °C; IR (KBr): 3321, 2968, 1673, 1596 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 3.82 (s, 6H, 2CH₃O), 4.28 (t, 1H, J = 2.4 Hz, NH), 6.73 (d, 2H, J = 2.4 Hz, H-1, H-5), 7.01–7.03 (m, 4H), 7.55–7.59 (m, 8H), 7.88–7.89 (m, 4H); ¹³C-NMR (DMSO-d₆): δ = 55.44, 56.34, 113.45, 115.46, 119.08, 129.22, 131.85, 132.46, 138.84, 142.35, 162.66, 187.68; MS (EI, 70 eV): m/z (%) = 702.8 (M⁺+1, 5), 532.9 (20), 371.9 (7), 181.9 (3), 170.9 (6), 135.0 (100), 107.0 (7), 77.0 (13); HRMS (EI): m/z calcd for C₃₂H₂₅Br₂N₅O₄: 701.0273; found: 701.0266.

2,6-Di(4-chlorophenyl)-4,8-di(4-nitrobenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2m): Orange color; m.p. 221–222 °C; IR (KBr): 3329, 2971, 1659, 1599 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.36 (t, 1H, J = 2.4 Hz, NH), 6.80 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.46–7.48 (m, 4H), 7.66 (dd, 4H, J = 2.4 Hz, J = 2.4 Hz), 8.04–8.07 (m, 4H) 8.30–8.32 (m, 4H); ¹³C-NMR (DMSO-d₆): δ = 56.71, 119.43, 122.98, 128.24, 128.95, 131.18, 137.88, 141.73, 142.64, 149.04, 162.24, 187.98; MS (EI, 70 eV): m/z (%) = 642.7 (M⁺, 4), 516.8 (18), 464.8 (16), 435.9 (22), 401.9 (20), 352.9 (16), 302.9 (12), 176.0 (10), 150.0 (100), 110.9 (58), 76.0 (32); HRMS (EI): m/z calcd for C₃₀H₁₉Cl₂N₇O₆: 643.0774; found: 645.0741.

2,6-Di(4-bromophenyl)-4,8-di(4-nitrobenzoyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2n): Yellow color; m.p. 271–272 °C; IR (KBr): 3329, 3073, 1650, 1601 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 4.36 (t, 1H, J = 2.4 Hz, NH), 6.80 (d, 2H, J = 3 Hz, H-1 and H-5), 7.59–7.63 (m, 8H), 8.06 (d, 4H, J = 8.4 Hz), 8.31 (d, 4H, J = 9 Hz); ¹³C-NMR (DMSO-d₆): δ = 56.65, 116.38, 119.80, 123.03, 131.23, 131.89, 137.93, 142.15, 142.65, 149.07, 162.28, 188.02; MS (EI, 70 eV): m/z (%) = 732.7 (M⁺, 6), 562.8 (36), 532.8 (21), 509.8 (8), 479.8 (14), 398.9 (20), 386.9 (13), 243.0 (10), 181.9 (23), 170.9 (37), 150.0 (100), 120.0 (22), 104.0 (63), 76.0 (56); HRMS (EI): m/z calcd for C₃₀H₁₉Br₂N₇O₆: 732.9744; found: 732.9739.

4,8-Diacetyl-2,6-di(4-chlorophenyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2o): Pale yellow color; m.p. 228–230 °C; IR (KBr): 3248, 2995, 1656, 1593 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 2.33 (s, 6H, 2CH₃), 4.05 (t, 1H, J = 2.4 Hz, NH), 6.41 (d, 2H, J = 2.4 Hz, H-1 and H-5), 7.47 (d, 4H, J = 9 Hz), 7.79 (d, 4H, J = 9 Hz); ¹³C-NMR (DMSO-d₆): δ = 24.22, 55.99, 119.08, 127.54, 128.69, 139.15, 141.85, 194.72; MS (EI, 70 eV): m/z (%) = 429.2 (M⁺,28), 386.1 (14), 359.1 (7), 332.1 (3), 303.1(100), 261.1 (30), 234.1 (77), 198.1 (15), 138.0 (36), 111.0 (57), 75.0 (12); HRMS (EI): m/z calcd for C₂₀H₁₇Cl₂N₅O₂: 429.0760; found: 429.0752.

4,8-Diacetyl-2,6-di(4-bromophenyl)-2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-diene (2p): Yellow color; m.p. 236–237 °C; IR (KBr): 3245, 3006, 1655, 1581 cm⁻¹; ¹H-NMR (DMSO-d₆): δ = 2.33 (s, 6H, 2CH₃), 4.06 (t, 1H, J = 2.4 Hz, NH), 6.40 (s, 2H, H-1 and H-5), 7.59–7.58 (m, 4H), 7.74–7.72 (m, 4H); ¹³C-NMR (DMSO-d₆): δ = 24.29, 55.92, 115.64, 119.46, 131.63, 139.19, 142.25, 194.78; MS (EI, 70 eV): m/z (%) = 519.1 (M⁺, 44), 476.1 (20), 449.1 (10), 422.0 (5), 347.1 (100), 305.1 (27), 280.1 (70), 266.1 (10), 182.0 (25), 157.0 (33), 143.0 (3), 91.1 (8); HRMS (EI): m/z calcd for C₂₀H₁₇Br₂N₅O₂: 518.9729; found: 518.9727. Crystal Data, C₂₀H₁₇Br₂N₅O₂, M = 519.19, monoclinic, crystal size = 0.130 × 0.090 × 0.020 mm, a = 11.766(2) Å, b = 10.114(2) Å, c = 17.408(3) Å, α = 90°, β = 103.573(8) °, γ = 90°, V = 2013.8(6)ų, T = 20.0 °C, space group: P2₁, Z = 4, calculated density = 1.712 g/cm³, no. of reflection measured 11322, θ_max = 51.1°, R1 = 0.0862 (CCDC 1888859) [59].

4. Conclusions

A new series of C₂-symmetric 2,3,6,7,9-pentaazabicyclo[3.3.1]nonane derivatives were synthesized in high yields through one-pot double Mannich-type reaction of Et₃N-catalyzed 3-oxo-2-arylhydrazonopropanals with double equivalents of ammonium acetate under three different heating platforms: conventional, ultrasound and microwave irradiation. Single crystal X-ray analysis supported the elucidation of the structures of the obtained products.

Supplementary Materials

Supplementary materials (¹H and ¹³C-NMR spectral sheets) are available online.

Author Contributions

H.M.A.-M, K.M.D. and W.M.T. designed the research, wrote the manuscript, edited and prepared it for publication. H.M.A.-M and K.M.D. were also responsible for the correspondence of the manuscript. W.M.T. and M.A.S. carried out the experimental part. All authors approved the final version.

Funding

This research work was funded by the University of Kuwait, grant number SC07/13.

Acknowledgments

Use of the facilities of Analab/SAF through research grants GS01/01, GS01/05, GS03/01 and GS03/08 at the University of Kuwait are gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.

Footnotes

Sample Availability: Samples of the synthesized compounds are available from the corresponding authors.

Figures, Scheme and Tables

Figure 1. Azabicyclo[3.3.1]nonane-based natural products.

Figure 2. ORTEP diagrams of the crystal structures of 2f (a), 2k (b), 2p (c).

Scheme 1. Suggested reaction mechanism for 2,3,6,7,9-pentaazabicyclo[3.3.1]nonanes 2.

Table 1

Optimization the dimerization condition of 3-oxo-2-arylhydrazonopropanals 1a with ammonium acetate ^a.

Scheme 1. Suggested reaction mechanism for 2,3,6,7,9-pentaazabicyclo[3.3.1]nonanes 2.

Run	Base-Catalyst (mol%)	Solvent	Conv. Heating		Sonication		MW Irradiation
			Yield b %	Time (h)	Yield b %	Time (min)	Yield b %	Time (min)
1	No catalyst	EtOH	trace	15	trace	120	trace	30
2	Et3N (15)	EtOH	70	4	82	60	87	5
3	Et3N (25)	EtOH	78 c	3	89 d	50	94	3
4	Et3N (30)	EtOH	71	3	85	60	90	4
5	Et3N (25) e	EtOH	66 e	3	73 e	50	80e	3
6	Et3N (25) f	EtOH	60 f	3	68 f	50	73f	3
7	Et3N (25)	MeOH	71	4	82	50	89	4
8	Et3N (25)	isopropanol	70	4	80	60	88	4
9	Et3N (25)	n-hexane	34	6	52	80	63	10
10	Et3N (25)	acetic acid	32	4	40	70	50	6
11	Et3N (25)	DMF	30	6	45	100	55	10
12	Et3N (25)	toluene	35	5	50	90	65	10
13	pyridine (25)	EtOH	20	4	28	60	35	5
14	DABCO (25)	EtOH	17	5	20	80	28	7
15	DBU (25)	EtOH	15	5	18	70	25	8
16	NaHCO3 (25)	EtOH	10	6	10	80	15	10
17	K2CO3 (25)	EtOH	10	5	12	90	15	10
18	NaOH (25)	EtOH	12	5	14	80	18	9

^a Reaction conditions: Arylhydrazonopropanal 1a (5 mmol), ammonium acetate (10 mmol) and base-catalyst (15~30 mol%) in solvent (7 mL) at reflux temperature for conventional heating 3~6 h, ultrasonic irradiation at 80 °C (110 W) for 50~100 min, or microwave irradiation at 80 °C (200 W) for 3~10 min. ^b isolated yield. ^c Yield was 20% after 50 min. ^d Yield was 35% after 15 min. ^e Compound 1a (5 mmol) and ammonium acetate (5 mmol) were used. ^f Compound 1a (10 mmol) and ammonium acetate (5 mmol) were used. Conv. = conventional, MW = microwave.

Table 2

Et₃N-catalyzed synthesis of 2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-dienes 2a–p.

Scheme 1. Suggested reaction mechanism for 2,3,6,7,9-pentaazabicyclo[3.3.1]nonanes 2.

Run	Products	R	Ar	Conv. Heating a		Sonication a		MW a Irradiation
				Yield b%	Time (h)	Yield b %	Time (min)	Yield b %	Time (min)
1	2a	4-FC6H4	4-ClC6H4	78	3	89	50	94	3
2	2b	4-FC6H4	4-BrC6H4	77	4	87	60	93	4
3	2c	C6H5	4-ClC6H4	70	3	81	50	89	4
4	2d	C6H5	4-BrC6H4	72	5	82	70	90	6
5	2e	C6H5	2-NO2C6H4	68	4	80	70	86	5
6	2f	4-ClC6H4	C6H5	71	3	83	40	90	3
7	2g	4-ClC6H4	4-BrC6H4	73	5	84	70	91	5
8	2h	4-BrC6H4	4-ClC6H4	86	4	87	70	92	5
9	2i	4-BrC6H4	4-BrC6H4	84	5	86	80	92	6
10	2j	4-OMeC6H4	C6H5	66	5	77	70	82	5
11	2k	4-OMeC6H4	4-ClC6H4	65	6	77	90	81	6
12	2l	4-OMeC6H4	4-BrC6H4	67	8	78	100	83	7
13	2m	4-NO2C6H4	4-ClC6H4	67	7	79	110	84	7
14	2n	4-NO2C6H4	4-BrC6H4	71	8	80	100	86	8
15	2o	CH3	4-ClC6H4	62	7	73	90	81	8
16	2p	CH3	4-BrC6H4	64	6	75	110	81	9

^a Reaction conditions: 3-Oxo-2-arylhydrazonopropanals 1a–p (5 mmol), ammonium acetate (10 mmol) and Et₃N (25 mol%) in EtOH (7 mL) at reflux temperature for conventional heating 3~8 h, ultrasonic irradiation at 80 °C (110 W) for 50~110 min, or microwave irradiation at 80 °C (200 W) for 3~9 min. ^b Isolated yields. Conv. = conventional, MW = microwave.