UDC:547.546 

SYNTHESIS OF 3-R-1,5-DINITRO-3-AZABICYCLO[3.3.1]NON-7-EN-6-IMINES BASED ON 2,4-DINITROANILINE

Mukhtorov L. G.¹, Aleksandrov N. S. ¹, Simonov R.V. ², Belocon D. A.⁴, Ivanova E.V. ⁴, Atroshchenko Y. M. ², Karimov M. B.³, Shakhkeldyan I. V.⁴

¹Youth research laboratory for the synthesis of organosilicon monomers and functional polymers, Tula State Pedagogical University L.N. Tolstoy,

²Center for technological excellence "Advanced chemical and biotechnologies" of Tula State Lev Tolstoy Pedagogical University,

³Branch of the National Research Technological University “MISiS”,

⁴Department of Chemistry. Tula State Pedagogical University by Leo Tolstoy.

Introduction. Obtaining new derivatives of 3-azabicyclononane is an important direction in the synthesis of organic compounds. It is known that 3-azabicyclononane is a key pharmacophore of a few plant alkaloids that are widely used in medicine. Among the synthetic heterocycles containing the 3-azabicyclo[3.3.1]nonane fragment, compounds with various types of biological activity were found: analgesic, anti-inflammatory, antimicrobial, fungicidal, anticancer, antioxidant, etc.

One of the promising classes of organic compounds is 3-azabicyclo[3.3.1]nonanes, which is due to their high physiological activity with a wide spectrum of action [1]. It is known that the azabicyclononane backbone is a structural fragment of many alkaloids with versatile biological activity [2]. Previously, 3-azabicyclo[3.3.1]nonanes were synthesized by the Mannich reaction with the participation of anionic adducts of various dinitroarenes [3–7]. However, so far it has not been possible to bring σ-adducts based on dinitroaniline into the Mannich condensation. In this work, we attempted to use 2,4-dinitroaniline as a substrate for the synthesis of heterocyclic systems.

This method of obtaining is characterizing by relative simplicity, the availability of reagents that makes it possible to carry out reaction to processes to 3-azabicyclo[3.3.1]nonane derivatives containing nitro groups that are promising for a further functionalization.

Experimental part

¹H and ¹³C NMR spectra were recorded on a Bruker DRX-500 spectrometer [600 MHz (¹H), 151 MHz (¹³C)] in DMSO-d₆. Chemical shifts (δ) are given in parts per million (ppm) relative to hexamethyldisiloxane spin- spin interaction constants (SSIC) (J) are expressed in hertz (Hz). High-resolution mass spectra were taken on a Bruker Daltonics Micro TOF II instrument (ionization method - ESI electrospray). IR spectra were recorded on an FSM 2202 Fourier spectrometer (Infraspec Rf). Conditions removed transmission, resolution 3.845 cm^-1. Number of scans-16 apodization Norton-Beer medium, range 4000 - 400 cm^-1. The sample was prepared by pressing into a KBr tablet, ratio 1:200. The reference spectrum-tablet KBr 200 mg was pressing in a vacuum mold tablet to thickness of 13 mm at a pressure of 200 bar.

The melting points of the compounds were measured by heating rate 4 deg/min on a Kofler table (Boetius). Silufol UV-254 light detection plates were used to determine retention factors (Rf), and eluent solution was prepared by mixing of toluene-acetone-hexane (4:1:1) by volume.

            General procedure for the synthesis of 3-substituted 1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imines 3(a,b) (see Fig. 1): 0.5 g (0.0027 mol) 2,4-dinitroaniline was dissolved in 24 ml of a mixture of dimethylacetamide, water, and acetone (10:1:1), 0.3 g (0.0054

mol) of KBH₄ in 5% Na₂CO₃ was added with stirring and cooling with ice water for 30 min. The temperature of the reaction mixture was maintained within the range of 0 – 5 °C. A preliminarily cooled amino methylation mixture (8 ml of a 32% formaldehyde solution and 0.005 mol of the corresponding amine hydrochloride) was added in portions to the resulting σ-adduct. Next, the reaction solution was acidified with a 20% orthophosphoric acid solution. After 30 min, the precipitate formed was filtered off, washed with water, and recrystallized from acetone.

3-Methyl-1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imine (3a): Yield 78%, melting point = 108-110 ^оС, R_f = 0.55. IR: v(C-H) 2980, 2951, 2892, 2820; v_as (NO₂) 1556; v_s (NO₂) 1373-1384; v(C=C) 1618-1637; v(N-H) 3240-3551. NMR ¹Н: δ 6.44-6.55 ppm (Н⁷), δ 7.55-7.60 ppm (H⁸) (³J = 10.0-10.2 Hz), δ 2.69-3.48 ppm.(H², H⁴, H⁹) (²J = 10.0-11.1 Hz), δ 2.37 ppm (СН₃). NMR ¹³С: δ_с С¹ (86.13); С² (55.95); С⁴ (57.39); С⁵ (90.03); С⁶ (189.26); С⁷ (148.01); С⁸ (130.49); С⁹ (40.28); СH₃ (44.38). Found m/z: 240.0874. [M+H]⁺. C₉H₁₂N₄O₄. Calculated, m/z: 241.0826.

3-Benzyl-1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imine (3b): Yield 63%, melting point = 58-60 ^оС, R_f = 0.43. IR: v(C-H) 2980, 2951, 2892, 2820 cm^-1; v_as (NO₂) 1556; v_s (NO₂) 1373-1384 cm^-1; v(C=C) 1618-1637 cm^-1; v(N-H) 3240-3551 cm^-1. NMR ¹Н: δ 6.44-6.55 ppm (Н⁷), δ 7.55-7.60 ppm. (H⁸) (³J = 10.0-10.2 Hz), δ 2.69-3.48 ppm (H², H⁴, H⁹) (²J = 10.0-11.1 Hz), δ 7.33 ppm (t, 2Н, Н-m), 7.28 (t, 1Н, Н-p) и 7.19 ppm (d, 2Н, Н-о) ppm (³J = 7.5 Hz), δ 3.76-3.81 ppm (СН₂) (²J = 13.3 Hz). NMR ¹³С: δ_с С¹ (86.14 ppm); С² (54.00 ppm); С⁴ (54.09 ppm); С⁵ (89.97 ppm); С⁶ (189.23 ppm); С⁷ (147.95 ppm); С⁸ (136.90 ppm); С⁹ (40.65 ppm); benzylic (Phenyl). (136.90, 129.11, 128.87, 127.95 ppm); α (59.96 ppm). Found, m/z: 316.0923 [M+H]⁺. C₁₅H₁₆N₄O₄. Calculated, m/z: 318.1079.

Results and Discussion

The synthesis of 3-R-1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imines based on 2,4-dinitroaniline 1 is a two-stage process (See Fig. 2). At the first stage, proceeding according to the nucleophilic mechanism, under the action of potassium tetrahydroborate on 1, the hydride ion is added to the aromatic ring of the nitro compound, leading to the formation of the dipotassium salt of 2,4-bis(acinitro)cyclohex-5-en-1-imine 2. In this case, the color of the reaction solution acquires a bright red color characteristic of Meisenheimer complex adducts. To reduce 2,4-dinitroaniline, the potassium tetrahydride is poorly soluble in organic solvents. To ensure good solubility of all reagents, the reaction was carried out in a mixture of aqueous-organic mixture solvents as dimethylacetamide, water, and acetone with a volume ratio of 10:1:1. For rapid and sufficiently complete conversion of 2,4-dinitroaniline to 2,4-bis(acinitro)cyclohex-5-en-1-imine dipotassium salt 2, a twofold excess of KBH₄ was used in all experiments compared to the stoichiometric amount. The reduction of 2,4-dinitroaniline with potassium tetrahydroborate proceeds with cooling at (0 – 5 °C) for 30 minutes.

The adduct 2 formed at the first stage is very labile; therefore, the next stage, electrophilic amino methylation according to Mannich, was carried out without its isolation by introducing a mixture of an aqueous solution of formaldehyde and hydrochloride of the corresponding primary amine into the reaction system. The amino methylation reaction also was carried out under cooling, maintaining the temperature in the range of (0 – 5 °C) for additional 30 min.

Then the reaction mixture was acidified with dilute orthophosphoric acid to pH 4–5, because of which the target products 3-R-1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imines 3(a,b)  precipitated from the reaction solution in the form of crystalline. The yield of crude products, depending on the substituent at the nitrogen atom of the heterocycle, was 65 – 70 %. The obtained compounds were purified by recrystallization in acetone.

The composition and structure of the obtained compounds 3(a,b) were determined by mass spectrometry and IR, ¹Н, ¹³С NMR, HSQС, HMBC, COZY spectroscopy (see Supplement part). In IR spectra of the analyzed substances, there is a band of stretching vibrations of the C=N bond at 1697 cm^-1. Intense bands at 1556, 1373 - 1384 cm^-1 refer to antisymmetric and symmetric vibrations of nitro groups. Stretching vibrations of the C=C bond appear at 1618-1637 cm^-1. The bands at 2980, 2951, 2892, 2820 cm^-1 characterize the stretching vibrations of the C-H bond. Bands of stretching vibrations of the N-H bond appear at 3240-3551 cm^-1.

When interpreting the ¹Н NMR spectra of compounds 3(a,b) we considered the experimental data from the literature [8,9], according to which the chair–chair conformation is characteristic of most heteroderivatives of azabicyclo[3.3.l]nonanes to a sharp decrease in 3,7-repulsion due to the flattening of the cyclohexene ring.

In the ¹H NMR spectra of solutions of compounds 3(a,b) in DMSO-d₆, there are characteristic signals of protons at the double bond in the form of doublets (³J = 10.0-10.2 Hz) with chemical shifts in the region of δ 6.44-6.55 ppm (H⁷) and δ 7.55-7.60 ppm (H⁸). The protons of the methylene groups of the bicyclic system (H², H⁴, H⁹) are diastereotopic; therefore, their signals mutually split into doublets with SSCC ²J = 10.0–11.1 Hz, lying in the region of δ 2.69–3.48 ppm. The protons of hydrocarbon radicals at the nitrogen atom give the expected types of signals. Singlet CH₃ - group of 3a is fixing at δ 2.37 ppm. The protons of the benzyl group of 3b form second groups of signals in the spectrum. Peaks at δ 7.33 (t, 2H, H-m), 7.28 (t, 1H, H-p) and 7.19 (d, 2H, H-o) ppm. With SSCC ³J = 7.5 Hz characterize the phenyl group. In the aliphatic region of the spectrum, two doublets appear (²J = 13.3 Hz) at δ 3.76–3.81 ppm. Protons of the CH₂ group. The molecular structure of compounds 3(a,b) is also confirmed by ¹³С NMR spectroscopy data. Thus, in the spectrum of compound 3a, signals from 9 nonequivalent carbon atoms are observed, of which 1 is primary, 3 are secondary, 2 are tertiary, and 3 are quaternary atoms. In the NMR spectrum using the (xxx) ART pulse sequence, the signal amplitudes of the quaternary atoms and CH₂ groups are positive (δс 189.26, 90.03, 86.13, 57.39, 55.95, 40.28 ppm), while the CH₃ and CH groups are negative (δс 184.01, 130.49, 44.38 ppm). In the weakest field at δс = 189.26 ppm the signal of the carbon atom of the imino group C⁶=NH is observed. To assign the signals of carbon and hydrogen atoms in the spectra, two-dimensional homo- (COSY) and heteronuclear (HSQC, HMBC) correlation spectra were recorded and tabulated (See Table 1 and Supplement part). The ¹H-¹H correlation spectrum contains peaks corresponding to geminal (²J H_a²/H_e², H_a⁴/H_e⁴, H_a⁹/H_e⁹), vicinal (³J H⁷/H⁸) and allyl (⁴J H⁸/H_a⁹) spin-spin interaction constants. Doublet signals of axial and equatorial protons of CH₂ groups bound by geminal constants are fixed in pairs at δ 3.12 (H_e²) and 2.69 (H_a²), 3.43 (H_e⁴) and 2.78 (H_a⁴), 3.47 (H_e⁹) and 3.04 (H_a⁹) ppm. In this case, the signals of the equatorial protons of the piperidine ring are broadened due to the long-range W-interaction through four bonds and are in a weaker field than narrow doublets of axial protons. The components of the doublet of the H⁸ proton (δ 7.55 ppm) are additionally split due to interaction with the axial proton H_a⁹ (⁴J = 2.4 Hz). The two-dimensional HSQC spectrum can be used to unambiguously determine the signals of carbon atoms C⁷ (148.01 ppm) С⁸ (130.49 ppm) and N-Me (44.38 ppm) which are related by direct constants and have one cross-peak each with H⁷ (δ 6.44 ppm) and H⁸ (δ 7.55 ppm) protons and CH₃ groups (148.01 ppm), C⁸ (130.49 ppm) and N-Me (44.38 ppm). Quaternary carbon atoms C¹ and C⁵, associated with electron-withdrawing nitro groups, include signals at δ_c 86.13 and 90.03 ppm, respectively. These signals can be distinguished by the corresponding cross-peaks H_a²/C¹, H_e²/C¹ and H_a⁴/C⁵, H_e⁴/C⁵ in the spectrum of HMBC. Characterized by two correlation peaks in the HSQC spectrum due to (SSIC) with axial and equatorial protons of the methylene groups, the signals of C², C⁴, and C⁹ carbon atoms of the piperidine ring are fixed at δ_c 40.28 ppm (C⁹), 55.95 ppm (C²), and 57.39 ppm (C⁴). These signals is distinguished by the presence of the ³J N-Me/C² and N-Me/C⁴ constants, which manifest themselves through the corresponding correlation peaks in the NMWR spectrum.

CONCLUSIONS

We have developed a simple and relivable preparative method for the synthesis of 3-substituted (N-H, N-Me, and N-CH₂-Ph) of 1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imines starting from the hydride adduct of 2,4-dinitroaniline. The chemical structure of the synthesized compounds was determined and studied by using high resolution ¹D and ²D NMR spectroscopy.

Declaration

The authors declare that they have no conflict of interest.

Table 1: ¹H and ¹³C chemical shifts signals for comparison of HMBC, HSQC and COSY NMR.

Figure 2. 2D ¹Н-¹³С correlation spectrum of NMR (600 MHz, in DMSO-d₆) (HMBC (b)): 3-methyl-1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imine (3а).

                                                                           REVIEWER: Manonov K.A.,

Candidate of Chemical Sciences, Associate Professor

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SYNTHESIS OF 3-R-1,5-DINITRO-3-AZABICYCLO[3.3.1]NON-7-EN-6-IMINES BASED ON 2,4-DINITROANILINE

We have synthesized new derivatives of 3-azabicyclo[3.3.1]nonane by Mannich condensation of the hydride σ-adduct of 2,4-dinitroaniline with formaldehyde and primary amines. The synthesis is carried out in two stages. In the first stage, the action of potassium tetrahydroborate (KBH₄) on a solution of  2,4-dinitroaniline resulted in the reduction of the C=C bond of the aromatic ring with the formation of a two-charged hydride diadduct. The obtained diadduct without isolation from the solution and under ice cooling was introduced into the Mannich condensation reaction with formaldehyde and primary amine solution. When the reaction mixture is acidified with dilute phosphoric acid to pH 4÷5, the target products are crystallized. After recrystallization from acetone, the yield of target products, depending on the substituent at the nitrogen atom, was 65–70%. This method of obtaining is characterized by relative simplicity, the availability of reagents that makes it possible to carry out reaction under a mild acidic condition to 3-azabicyclo[3.3.1]nonane derivatives containing nitro groups that are promising from the point of view of further functionalization. The structure of the obtained compounds was proved by IR, ¹H-, ¹³C-, two-dimensional correlation NMR spectroscopy, as well as high-resolution mass spectrometry (HRMS) data.

Keywords: hydride adducts, Mannich condensation, 2,4-dinitroaniline, 3-R-1,5-dinitro-3-azabicyclo[3.3.1]non-7-en-6-imine.

Information about the authors: Mukhtorov Loik Gurgovich – Tula State Pedagogical University named after L.N. Tolstoy, PhD, research fellow of the “Youth Research Laboratory for the Synthesis of Organosilicon Monomers and Functional Polymers. Address: 300026, Tula, Russia, Lenin Ave., 125. Tel.: +7(953)-188-46-16. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Aleksandrov Nikita Sergeevich – Tula State Pedagogical University named after L.N. Tolstoy, laboratory assistant-researcher of the “Youth Research Laboratory for the Synthesis of Organosilicon Monomers and Functional Polymers. Address: 300026, Tula, Russia, Lenin Ave., 125. Phone: +7(915)-789-54-96. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Simonov Roman Viktorovich - Tula State Pedagogical University named after L.N. Tolstoy, research fellow of the Center for Technological Excellence "Advanced Chemical and Biotechnology named after S.S. Gitis". Address: 300026, Tula, Russia, Lenin Ave., 125. Phone: +7 (919) 0870595. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Belokon Danila Alekseevich - Tula State Pedagogical University named after L.N. Tolstoy, bachelor of the final year of the program "Medical and Pharmaceutical Chemistry", laboratory assistant of the Department of Chemistry. Address: 300026, Tula, Russia, Lenin Ave., 125. Phone: +7 960 602-91-48. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Ivanova Evgenia Vladimirovna – Tula State Pedagogical University named after. L.N. Tolstoy, Ph.D., Associate Professor of the Department of Chemistry. Address: 300026, Tula, Russia, Lenin Ave., 125. Phone: +7(920)-273-61-51. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Atroshchenko Yuri Mikhailovich – Tula State Pedagogical University named after. L.N. Tolstoy, Doctor of Chemical Sciences, Professor, Chief Researcher of the Center for Technological Excellence “Advanced Chemical and Biotechnologies named after. S.S. Gitis". Address: 300026, Tula, Russia, Lenin Ave., 125. Phone: +7(910)-945-69-82. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Karimov Mahmadkul Boboevich – Tajik National University, D.Sc. (Chemistry), Professor, Department of Organic Chemistry. Address:734025, Dushanbe, Tajikistan, Rudaki Ave., 17. Phone: +992(919)41-02-41. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Shakhkeldyan Irina Vladimirovna – Tula State Pedagogical University named after L.N. Tolstoy, D.Sc. (Chemistry), Professor, Dean of the Faculty of Natural Sciences. Address: 300026, Tula, Russia, Lenin Ave., 125. Phone: +7(915)691-26-80. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Article received 15.04.2024

Approved after review 03.06.2024

Accepted for publication 06.09.2024