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Article

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

by
Hamad M. Al-Matar
1,*,
Kamal M. Dawood
2,*,
Wael M. Tohamy
3 and
Mona A. Shalaby
1
1
Chemistry Department, Faculty of Science, University of Kuwait, P.O. Box 5969, Safat 13060, Kuwait
2
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
3
Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo 12622, Egypt
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(6), 1110; https://doi.org/10.3390/molecules24061110
Submission received: 25 February 2019 / Revised: 13 March 2019 / Accepted: 14 March 2019 / Published: 20 March 2019
(This article belongs to the Collection Heterocyclic Compounds)
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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.

Graphical Abstract

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, NaHCO3, K2CO3, 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) Å3, 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) Å3, 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)Å3, T = 20.0 °C, space group: P21, Z = 4, calculated density = 1.712 g/cm3, no. of reflection measured 11322, θmax = 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.

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Sample Availability: Samples of the synthesized compounds are available from the corresponding authors.
Molecules 24 01110 g001 550
Figure 1. Azabicyclo[3.3.1]nonane-based natural products.
Figure 1. Azabicyclo[3.3.1]nonane-based natural products.
Molecules 24 01110 g001
Molecules 24 01110 g002 550
Figure 2. ORTEP diagrams of the crystal structures of 2f (a), 2k (b), 2p (c).
Figure 2. ORTEP diagrams of the crystal structures of 2f (a), 2k (b), 2p (c).
Molecules 24 01110 g002
Molecules 24 01110 sch001 550
Scheme 1. Suggested reaction mechanism for 2,3,6,7,9-pentaazabicyclo[3.3.1]nonanes 2.
Scheme 1. Suggested reaction mechanism for 2,3,6,7,9-pentaazabicyclo[3.3.1]nonanes 2.
Molecules 24 01110 sch001
Table
Table 1. Optimization the dimerization condition of 3-oxo-2-arylhydrazonopropanals 1a with ammonium acetate a.
Table 1. Optimization the dimerization condition of 3-oxo-2-arylhydrazonopropanals 1a with ammonium acetate a.
Molecules 24 01110 i001
RunBase-Catalyst (mol%)SolventConv. HeatingSonicationMW Irradiation
Yield b %Time (h)Yield b %Time (min)Yield b %Time (min)
1No catalystEtOHtrace15trace120trace30
2Et3N (15)EtOH7048260875
3Et3N (25)EtOH78 c389 d50943
4Et3N (30)EtOH7138560904
5Et3N (25) eEtOH66 e373 e5080e3
6Et3N (25) fEtOH60 f368 f5073f3
7Et3N (25)MeOH7148250894
8Et3N (25)isopropanol7048060884
9Et3N (25)n-hexane34652806310
10Et3N (25)acetic acid3244070506
11Et3N (25)DMF306451005510
12Et3N (25)toluene35550906510
13pyridine (25)EtOH2042860355
14DABCO (25)EtOH1752080287
15DBU (25)EtOH1551870258
16NaHCO3 (25)EtOH10610801510
17K2CO3 (25)EtOH10512901510
18NaOH (25)EtOH1251480189
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
Table 2. Et3N-catalyzed synthesis of 2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-dienes 2a–p.
Table 2. Et3N-catalyzed synthesis of 2,3,6,7,9-pentaazabicyclo[3.3.1]nona-3,7-dienes 2a–p.
Molecules 24 01110 i002
RunProductsRArConv. Heating aSonication aMW a Irradiation
Yield b%Time (h)Yield b %Time (min)Yield b %Time (min)
12a4-FC6H44-ClC6H47838950943
22b4-FC6H44-BrC6H47748760934
32cC6H54-ClC6H47038150894
42dC6H54-BrC6H47258270906
52eC6H52-NO2C6H46848070865
62f4-ClC6H4C6H57138340903
72g4-ClC6H44-BrC6H47358470915
82h4-BrC6H44-ClC6H48648770925
92i4-BrC6H44-BrC6H48458680926
102j4-OMeC6H4C6H56657770825
112k4-OMeC6H44-ClC6H46567790816
122l4-OMeC6H44-BrC6H467878100837
132m4-NO2C6H44-ClC6H467779110847
142n4-NO2C6H44-BrC6H471880100868
152oCH34-ClC6H46277390818
162pCH34-BrC6H464675110819
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.

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Al-Matar, H.M.; Dawood, K.M.; Tohamy, W.M.; Shalaby, M.A. Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms. Molecules 2019, 24, 1110. https://doi.org/10.3390/molecules24061110

AMA Style

Al-Matar HM, Dawood KM, Tohamy WM, Shalaby MA. Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms. Molecules. 2019; 24(6):1110. https://doi.org/10.3390/molecules24061110

Chicago/Turabian Style

Al-Matar, Hamad M., Kamal M. Dawood, Wael M. Tohamy, and Mona A. Shalaby. 2019. "Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms" Molecules 24, no. 6: 1110. https://doi.org/10.3390/molecules24061110

APA Style

Al-Matar, H. M., Dawood, K. M., Tohamy, W. M., & Shalaby, M. A. (2019). Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms. Molecules, 24(6), 1110. https://doi.org/10.3390/molecules24061110

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