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Background:
Hypothesis

Treatment of Substandard Rocket Fuel 1,1-Dimethylhydrazine via Its Methylene Derivative into Heterocycles Based on Pyrrolo-[3,4c]Quinolines, Cyclododeca[b]piran and Pyrrole

by
Elizaveta Ivanova
1,
Maxim Maryasov
1,
Vera Andreeva
1,
Margarita Osipova
1,
Tatyana Vasilieva
1,
Alexey Eremkin
1,
Olga Lodochnikova
2,
Denis Grishaev
3 and
Oleg E. Nasakin
1,*
1
Organic and Pharmaceutical Chemistry Department, ssUlyanov Chuvash State University, Moskovsky Prospect, 15, 428015 Cheboksary, Russia
2
Organic and Pharmaceutical Chemistry Department, Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov Streed, 8, 420088 Kazan, Russia
3
Organic and Pharmaceutical Chemistry Department, Scientific and Educational Center Pharmacy, Kazan Federal University, Paris Commune Street, 9, 296100 Kazan, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(17), 13076; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713076
Submission received: 28 June 2023 / Revised: 2 August 2023 / Accepted: 11 August 2023 / Published: 22 August 2023
(This article belongs to the Section Physical Chemistry and Chemical Physics)
Browse Figures
Versions Notes

Abstract

:
1,1-Dimethylhydrazine (Heptil, rocket fuel (UDMH)) is characterized by extremely high toxicity, teratogenicity and the ability to constantly absorb water from the atmosphere, losing its energy characteristics. In this regard, as well as due to the alternative fuel (“Angara”) transition, there is a need for UDMH utilization in huge amounts. A more benign approach involves its immediate reaction with a formalin solution to form 1,1–dimethyl-2-methylene hydrazone (MDH), which is significantly less toxic by an order of magnitude. MDH can then be polymerized under acidic conditions, and the resulting product can be burned, yielding a substantial amount of nitrogen oxides. We propose an alternative to incineration by involving MDH in organic synthesis. We studied the reactions of MDH and its analog N,N-dimethyl-2-(methylenamino)ethane-1-amine (MDEA) with available CH-acids: tetracyanoethylated ketones (TCEKs) based on cyclohexanone, 4-propylcyclohexanone, 2-methylcyclohexanone, cyclododecanone and tetracyanoethane. The structures synthesized were confirmed by IR, 1H, 13C NMR and mass spectroscopy methods. MDH-based adducts were also identified by X-ray structural analysis. TCEKs and MDH, as well as TCEK based on cyclohexanone and MDEA, form bi- and tricyclic structures: pyrrolo [3,4c]-quinolines (using TCEKs based on cyclohexanone and 4-propylcyclohexanone), epiminomethanoquinoline-3,4-dicarbonitrile (using TCEK based on 2-methylcyclohexanone) and cyclododec[b]pyran-3,4-dicarbonitrile (using TCEK based on cyclododecanone). MDH and TCNEH2 formed a pyrrole derivative. Thus, we synthesized the structures that are of interest for molecular design and pharmaceutical chemistry.

Graphical Abstract

1. Introduction

Heptil (unsymmetric dimethylhydrazine, UDMH) is actively used worldwide as a fuel for rocket engines. At the same time, it constantly loses its properties due to uncontrolled absorption of moisture that cannot be separated by rectification. UDMH is an extremely toxic compound (Hazard class 1), which complicates its transportation for treatment. During disposal by incineration, some oxidation products that are much more toxic than the original substance are produced. The safest way to neutralize it is its instantaneous interaction with a formalin solution to form a less toxic 1,1-dimethyl-2-methylene hydrazone (MDH) [1,2], that is then polymerized in an acidic medium, with the resulting product incinerated producing a huge amount of nitrogen oxides. This study aims to identify the synthetic abilities and practical applications of MDH (instead of incineration). We would like to draw the chemical community’s attention to this metastable compound, which is promising for use in molecular design, as well as in pharmaceutical and medicinal chemistry. We have studied the reactions of MDH with polycyano-containing CH-acids. As the latter, available tetracyanoethylated ketones (TCEKs) were used, which are the most stable and prone to cascade transformations, and they have a high synthetic potential (readily available CH-acids, pKa 2.8–3.6 [3]). The main properties of MDH [1] suggested catalytic intramolecular cyclizations with the formation of a fragment—pyrrolidin-2-one.
This fragment represents a group of inhibitors belonging to various enzyme classes, including HIV-1 integrase [4] (an enzyme responsible for catalyzing the integration of HIV-1 viral DNA into the host cell chromosome), tyrosine kinase [5] (an enzyme that facilitates the transfer of the phosphate group from ATP to tyrosine residue), and telomerase [6] (an enzyme that adds a specific sequence to the end of the DNA chain and stabilizes the chromosomes). Additionally, it serves as a structural component in agonists, namely chemical compounds which elicit biological responses upon interaction with receptors. Examples of such agonists include serotonin [7], chemokine [8] (a peptide that regulates leukocyte movement and their migration from the bloodstream into tissues), and endothelin [6] (a potent vasoconstrictor receptor composed of 21 amino acids). Furthermore, the compound pyrrolidin-2-one is utilized as an active ingredient in drugs employed for the treatment of disorders associated with neurological function, memory and mental fatigue [9] (Figure 1).
The methylene derivative of N,N-dimethyl-2-(methylenamino)ethane-1-amine (MDEA), known as N,N-dimethylethane-1,2-diamine (DMEDA), possesses spaced reaction centers and undergoes reactions with TCEKs similar to MDH. Furthermore, this fragment is integral to medications employed in the treatment of acute pancreatitis [10] and the mitigation of drug resistance in cancer cells [11] (Figure 2).
The compounds synthesized in this study, derived from TCEKs, MDH, and MDEA, exhibit structural similarities to well-known drugs due to the presence of hydroquinoline moieties (highlighted by the green circle in Figure 3) and pyrrole moieties (highlighted by the blue circle in Figure 3).
As a result, pyrrolo[3,4c]-quinolines (obtained through MDH and TCEK reactions using cyclohexanone and 4-propylcyclohexanone) and epiminomethanoquinoline-3,4-dicarbonitrile (synthesized via MDH and TCEK reactions using 2-methylcyclohexanone) exhibit structural similarities to compounds utilized in the treatment of neurodegenerative diseases (Figure 3) (Ropinirole [12], Pergolide [13,14], Lisuride [15,16,17] and Apofomin [18]).
Cyclododeca[b]pyran-3,4-dicarbonitrile (synthesized through the use of 2-methyl-5-decylhexane-2,5-dione and trichloroethyl ketone based on cyclododecanone) is expected to find application as an antiviral agent, owing to the presence of the pyran ring, which is a common structural motif in biologically active antiviral compounds [19] (Figure 4).

2. Results

2.1. Results of the Syntheses

2.1.1. Structures Based on MDH and MDEA with TCEKs 1a,b,c and 2

  • pyrrolo[3,4c]-quinolines 9a,b (TCEKs 1a,b with MDH) (see Figure 6, Section 3 Discussion);
  • 9′ (TCEK 1a with MDEA) (see Figure 6, Section 3).
  • 8a,4-(epiminomethano)quinoline-3,4-dicarbonitrile 11c (TCEK 1c with MDH) (see Figure 7, Section 3);
  • cyclodode[b]pyran-3,4-dicarbonitrile 8 (TCEK 2 with MDH) (see Figure 9, Section 3).

2.1.2. Structures Based on MDH with TCNEH2

  • pyrrole derivative 12 (see Figure 14, Section 3);
The structures obtained were determined by IR, 1H, 13C NMR and mass spectroscopy (the description of some chemical shifts see in Section 3). The data are shown in the table below (Table 1) (see Figures S1–S18 in Supplementary Materials):

2.1.3. Elemental Analysis of the Structures Obtained

  • 3-Amino-5-(dimethylamino)-1-oxo-4,5,6,7,8,9-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a,9b-dicarbonitrile (9a). Found: C 60.28; H 6.31; N 28.05. C15H18N6O. Calculated %: C 60.39; H 6.08; N 28.17.
  • 3-Amino-5-(dimethylamino)-1-oxo-8-(propyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a,9b- dicarbonitrile (9b). Found: C 63.48; H 7.13; N 24.65. C18H24N6O. Calculated %: C 63.51; H 7.11; N 24.69.
  • 3-Amino-5-(2-(dimethylamino)ethyl-1-oxo-4,5,6,7,8,9-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a,9b-dicarbonitrile (9′) Found: C 62.53 H 6.75 N 25.80. C17H22N6O. Calculated %: C 62.56; H 6.79; N 25.75.
  • 2-(Dimethylamino)-4a-methyl-10-oxo-5,6,7,8-tetrahydro-1H-8a,4-(epimino)quinoline-3,4(4aH)-dicarbonitrile (12c). Found: C 63.08; H 6.69; N 24.55. C15H19N5O. Calculated %: C 63.14; H 6.71; N 24.54.
  • (E)2-Amino-6,7,8,9,10,11,12,13-octahydro-5H-cyclododeca [b]pyran-3,4-dicarbonitrile (8). Found: C 72.03; H 7.42; N 14.80. C17H21N3O. Calculated %: C 72.06; H 7.47; N 14.83.
  • 5-Amino-1-(dimethylamino)-1,2-dihydro-3H-pyrrole-3,3,4-tricarbonitrile (12). Found, %: C 53.61; H 4.72; N 41.67. C9H10N6. Calculated %: C 53.46; H 4.98; N 41.56.

2.1.4. Crystal Data on the Structures 9a,b, 12c and 8 (See the Descriptions in Section 3, Figures 8–10 and 12)

  • Crystal Data for 9a: C15H18N6O (M =298.35 g/mol): triclinic, space group P-1 (no. 2), a = 13.9756(12) Å, b = 15.0773(15) Å, c = 18.0923(13) Å, α = 112.010(8)°, β = 93.942(7)°, γ = 112.380(9)°, V = 3167.3(5) Å3, Z = 8, T = 104(7) K, μ(Cu Kα) = 0.683 mm−1, Dcalc = 1.251 g/cm3, 34121 reflections measured (5.436° ≤ 2Θ ≤ 156.656°), 12415 unique (Rint = 0.1673, Rsigma = 0.1628) which were used in all calculations. The final R1 was 0.0845 (I > 2σ(I)) and wR2 was 0.2282 (all data). CCDC number 2152262.
  • Crystal Data for 9b: C22H32N6O3 (M =428.53 g/mol): triclinic, space group P-1 (no. 2), a = 9.42370(10) Å, b = 11.97650(10) Å, c = 11.99720(10) Å, α = 111.2460(10)°, β = 111.1820(10)°, γ = 93.9690(10)°, V = 1145.11(2) Å3, Z = 2, T = 102.2(9) K, μ(Cu Kα) = 0.690 mm−1, Dcalc = 1.243 g/cm3, 33743 reflections measured (8.14° ≤ 2Θ ≤ 153.026°), 4548 unique (Rint = 0.0349, Rsigma = 0.0172) which were used in all calculations. The final R1 was 0.0422 (I > 2σ(I)) and wR2 was 0.1101 (all data). CCDC number 2152263.
  • Crystal Data for 12c: C15H19N5O (M =285.35 g/mol): triclinic, space group P-1 (no. 2), a = 7.5867(2) Å, b = 9.1339(3) Å, c = 10.8470(4) Å, α = 76.621(3)°, β = 82.305(3)°, γ = 81.452(3)°, V= 719.26(4) Å3, Z = 2, T = 100(1) K, μ(Cu Kα) = 0.703 mm−1, Dcalc = 1.318 g/cm3, 17589 reflections measured (8.424° ≤ 2Θ ≤ 152.906°), 2865 unique (Rint = 0.0345, Rsigma = 0.0220) which were used in all calculations. The final R1 was 0.0399 (I > 2σ(I)) and wR2 was 0.0993 (all data). CCDC number 2152264.
  • Crystal Data for 8: for C17H21N3O (M =283.37 g/mol): triclinic, space group P-1 (no. 2), a = 8.5574(5) Å, b = 9.7008(6) Å, c = 9.7930(4) Å, α = 102.032(4)°, β = 103.106(4)°, γ = 101.505(5)°, V = 747.97(7) Å3, Z = 2, T = 99.9(10) K, μ(Cu Kα) = 0.632 mm−1, Dcalc = 1.258 g/cm3, 7141 reflections measured (9.618° ≤ 2Θ ≤ 153.2°), 2981 unique (Rint = 0.0614, Rsigma = 0.0595) which were used in all calculations. The final R1 was 0.0821 (I > 2σ(I)) and wR2 was 0.2326 (all data). CCDC number 2152265.
See crystal data and structure refinement for 9a, 9b, 12c and 8 in the table below (Table 2):

3. Discussion

It appears that MDH easily reacts with TCEKs via all its structural fragments: Methylene group (A) ensures cyclization to pyrrolidin-2-one (F) and the dimethylamine fragment (B). We found out that MDH decomposed during its interactions, forming original compounds (E) and degraded further into dimethylamine and formaldoxime (C). In turn, the intermediate in the C-direction was able to produce an appropriative salt (direction D, Figure 5).
All of the directions above are implemented in the examples below.
All of the syntheses were carried out in a basic medium of ethyl acetate at room temperature. Chemical TCEK transformations [20] in an alkaline medium are described in our earlier publication [21]. However, spiro compounds obtained there [21] differed from the structures presented herein. The structures obtained by morpholine catalysis are also different [22].
Thus, 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarbonitrile 1a, 1-(2-oxo-5-propylcyclohexyl)ethane-1,1,2,2-tetracarbonitrile 1b with MDH (1′a) (intermediates 2a,b–8a,b) and cyclohexanone derivative 1a with MDEA (1′b) (intermediates 2′–8′) interacted according to the same scheme (Figure 6). The derivative of 2-methylcyclohexanone 1c with MDH (1′a) undergoes chemical transformations identical to TCEKs 1a and 1b (intermediates 2c–5c) until the moment of rearrangement.
Presumably, the first stage of the interaction is the same for three TCEKs 1a–c and is a Michael-type attachment of the CH-acid center 1a–c to 1′a,b. The resulting Michael-type adducts 2a–c, 2′ are likely to undergo intermolecular cyclization transformations catalyzed by alkali. Zwitterions 3a–c, 3′ via intermediates 4a–c, 4′ transform into heterocycles 5a–c, 5′. The rearrangement of the 2-methylcyclohexanone derivative 5c is carried out according to another scheme (Figure 7). Tricycles 6a,b, 6′ open into amides 7a,b, 7′. Thorpe–Ziegler type cyclization [23] in γ-lactam leads to pyrrolo[3,4-c]quinolines MDH-based 9a (m/z 299.1620) (see Figure S3 in Supplementary Materials), 9b (m/z 341.2090) (see Figure S6 in Supplementary Materials) and MDEA-based 9′ (m/z: 326.0000) (see Figure S9 in Supplementary Materials) (Figure 6).
The substituents in the structures mentioned above are presented in the table below (Table 3).
Ijms 24 13076 i012
The absence of a proton in the α-position of TCEK 1c causes a different direction of the chemical process. Therefore, after the Thorpe–Ziegler type cyclization (intermediate 5c, Figure 6), we assume an electron density redistribution during the rearrangement. This may lead to the opening of a six-membered cycle 7c and to the cyclization of diazene 8c into 1,2-diazepine 9c (Figure 7). The activated N=N+ bond promotes cyclization into 1,2-diazepine, according to the publication [24]. The transition of N-aminopyridine derivatives to a diazepine intermediate is also described in the article [25]. The alkaline medium is likely to promote the N-N bond cleavage of the seven-membered cycle 9c with subsequent cyclization into α–(N,N-dimethylamino)tetrahydropyridine 12c by analogy with the publication [26]. Prussic acid elimination during the cyclization of intermediate 11c was confirmed by a qualitative reaction to Prussian blue (see Section 3).
Previously, we proposed the formation of the desired product 12c through the decomposition of MDH into prussic acid and dimethylamine (DMA), which was subsequently added to the terminal carbonitrile of TCEK 1c. The hypothesis of MDH decomposition into DMA was tested using gas chromatography (refer to Section 4). The gas-chromatographic analysis results showed no presence of DMA in the reaction mixture. The retention time of DMA synthesized using a standard procedure [27] was observed at 120 s. The retention times of the gases released during the reaction of TCEK 1c and MDH were 30 s and 7 min. Therefore, the formation of compound 12c according to the proposed schemes (Figure 6 and Figure 7) is more probable.
The unusual structures of the resulting compounds were determined using proton nuclear magnetic resonance (1H NMR) (see Figures S1, S4, S7, S10, S13 and S16 in Supplementary Materials), carbon nuclear magnetic resonance (13C NMR) (see Figures S2, S5, S8, S11, S14 and S17 in Supplementary Materials), and X-ray diffraction analysis (Table 1 and Table 2, Section 2. Results). Descriptions of the crystal structures of the resulting compounds 9a, 9b and 11c are provided below (Figure 8, Figure 9 and Figure 10).
Compound 9a is represented in the crystal by four independent molecules with the same geometry shown in Figure 8.
In crystal 9b, disorder was found in the fragment containing a propyl substituent, a chiral center at C11 and a methylene group at C12. This indicates the presence in the crystal of two diastereomers differing in the configuration of the C11 atom (Figure 9).
The macrocyclic cyclododecanone derivative 2 is stable and does not react with MDH. However, the latter may potentially deprotonate TCEK 2. Subsequently, salt 3 is expected to undergo transformation into tricyanovinyl intermediate 5, following a similar process described in publication [28]. Intermediate 5 then undergoes tautomerization to form enolate 6 under basic conditions, which facilitates cyclization to yield pyran derivative 8 (m/z 283.1700) (see Figure S15 in Supplementary Materials) (Figure 11). The presence of prussic acid was confirmed through a qualitative reaction with Prussian blue (refer to Section 4).
To evaluate the efficacy of MDH as a catalyst for TCEK 2-related reactions, we performed a control synthesis of compound 8 without the inclusion of MDH in the reaction mixture (refer to Section 4). The formation of the desired product 8 was observed within 24 h, whereas the MDH-catalyzed reaction proceeded within 30 min.
The structure of the resulting compound 8 is shown below (Figure 12).
DMH reacts with the tetracyanoethylene (TCNE) released at the hydrogen atom of the methylene group. In our earlier publication [29], we reported that the low-yield tricyanohydrazine derivatives 9 were obtained, known as potential antimicrobial dyes and photosensitizers (Figure 13).
The MDH-reaction at the CH-acidic center enables the incorporation of MDH in the synthesis with tetracyanoethane (TCNEH2). In contrast to our previous publication [29], which described the addition of MDH to tetracyanoethylene (TCNE) through methylene-active hydrogen, the reaction of MDH with TCNEH2 leads to the formation of cyclic pyrrole derivative 12 (m/z 203.1047) (see Figure S18 in Supplementary Materials), as depicted in the proposed chemical transformation scheme presented below (Figure 14).
As mentioned above (Section 1), the resulting products 9a,b, 9′, 12c, 8 contain the moieties that are similar with the structures of well-known drugs used for the treatment of neurodegenerative and viral diseases. Therefore, the compounds obtained will be tested on biological activity in these areas.

4. Materials and Methods

The syntheses involving the release of hydrogen cyanide (prussic acid) should be conducted with the provision of a gas vent, an absorption flask and performed under a properly functioning hume hood. It is essential to use protective eyewear and latex gloves.
All reagents were procured from commercial vendors and employed without undergoing additional purification. Among them there is non-marketable rocket fuel based on unsymmetrical dimethylhydrazine (“Chemical Point ug”, Deisenhofen, Germany), formalin (“Across Organics”, Geel, Belgium), cyclohexanone (“Qingdao Honghao Chemical Co., Ltd.”, Shandong, China), 4-propyl cyclohexanone (“Santa Cruz Biotechnology”, Dallas, TX, USA), 2-methylcyclohexanone (“Across Organics”, Geel), cyclododecanone (“Hangzhou Keying Chem Co., Ltd.”, Hangzhou, China), ethyl acetate (“Across Organics”, Geel), tetracyanoethylene (“Across Organics”, Geel), iron sulfate (“Across Organics”, Geel), potassium hydroxide (“Across Organics”, Geel).
The progress of reactions and the purity of products were monitored via thin-layer chromatography (TLC) on Sorbfil plates (“Sorbfil”, Krasnodar, Russia).
Visualization of spots was achieved under ultraviolet (UV) light, upon treatment with iodine vapor, or through heating. Melting and decomposition points were determined using the Optimelt MPA100 apparatus (“Optimelt”, Danbury, Connecticut). Infrared (IR) spectra were obtained using the FSM-1202 spectrometer equipped with Fourier transform technology, with samples dispersed in Nujol. Proton nuclear magnetic resonance (1H NMR) and carbon-13 nuclear magnetic resonance (13C NMR) spectra were acquired with the provision of the Carr−Purcell−Meiboom−Gill (CPMG) pulse sequence, employing DMSO-d6 solvent and utilizing the TMS internal standard. The measurements were conducted on a Bruker AVANCE 400 WB spectrometer (“Bruker”, Hanau, Germany) operating at the frequencies of 400.13 MHz for 1H and 100.61 MHz for 13C.
HRMS mass spectra of 9a, 9b, 12c and 8 were acquired using the quadrupole time-of-flight (t, qTOF) AB Sciex Triple TOF 5600 mass spectrometer (AB SCIEX PTE. Ltd., Singapore) equipped with a turbo-ion spray source. The nebulizer gas used was nitrogen, and the ionization polarity was positive (+). The needle voltage was set at 5500 V. The spectra were recorded in the time-of-flight mass spectrometry (TOF MS) mode with a collision energy of 10 eV, declustering potential of 100 eV, and a resolution exceeding 30,000 full-width half-maximum. Sample solutions with an analyte concentration of 5 μmol/L were prepared by dissolving the test compounds in methanol (hypergrade for LC-MS, Merck).
An analytical reversed-phase HPLC was used for determination of uncalibrated purity of the compounds 7 and 28 and conducted using an Atlantis T3 C18 column (5µm, 150 × 4.6 mm); eluent A, 1.2% solution of triethylamine in water; eluent B CH3CN; and the gradient elution (0 min A:B = 85:15; 15 min A:B = 65:35; 21 min A:B = 65:35) flow rate was 1.0 mL/min. HPLC analysis was performed at 40 °C during 21 min at 311 nm.
Mass spectra of compound 9′ were acquired using the quadrupole gas-chromatography mass spectrometer (GCMS-QP2020 NX (“Shimadzu”, Duisburg, Germany)). Gas chromatograph was equipped with the column SH-I-5MS. Dimethyl polysiloxane was utilized as the stationary phase. A sample solution with an analyte concentration of 5 μmol/L was prepared by dissolving the test compound in isopropanol.
Data sets for single crystals 9a, 9b, 12c and 8 were collected using the Rigaku Xta-Lab Synergy S instrument with a HyPix detector and a microfocus X-ray tube PhotonJet, utilizing Cu Kα radiation (1.54184 Å) at low temperature. The images were indexed and integrated using the data reduction package CrysAlisPro (“Rigaku Oxford Diffraction CrysAlisPro”, Oxford, UK). The data were corrected for systematic errors and absorption using the ABSPACK module: numerical absorption correction based on Gaussian integration over a polyhedron crystal model, and empirical absorption correction based on spherical harmonics according to the symmetry point group using equivalent reflections. The GRAL module was used for analyzing systematic absences and determining the space group. The structure was solved by direct methods using SHELXT [30] and refined by least squares with a full matrix on F2 using SHELXL [31]. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in calculated positions and refined as riding atoms. Figures were generated using Mercury 4.1 software [32]. Crystals were obtained by the slow evaporation method. Crystal data and refinement parameters were summarized in Table 1 (Section 2).
Gases were identified using the Crystal 5000.1 laboratory gas chromatograph (CJSC SKB “Chromatek”, Yoshkar-Ola, Russia) with a thermo-electronic detector and the Chromatek-Analyst chromatographic data processing system under the following conditions: column temperature 100 °C; evaporator temperature 120 °C; detector temperature 390 °C; carrier gas flow rate (nitrogen) 20 cm3/min; hydrogen flow rate 14 cm3/min; and air flow rate 200 cm3/min.
Qualitative reaction to prussic acid. Firstly, 1–3 drops of a 40% solution of ferrum (II) sulfate were added to an absorption flask placed on a magnetic stirrer containing a dilute solution of potassium hydroxide while prussic acid gas was introduced through the gas vent. The solution was vigorously stirred and heated to boiling. Upon cooling of the reaction mixture, a 10% hydrochloric acid solution was added to achieve a slightly acidic reaction on universal paper. The appearance of blue staining and the formation of a blue precipitate confirmed the liberation of prussic acid during the reactions (Figure 7 and Figure 11, Section 3).
N,N-dimethyl-2-methylenehydrazone (MDH) and N,N-dimethyl-2-(methylene-amino)ethan-1-amine (MDEA) were synthesized following a standard procedure [2] yielding 36% (3.89 g) and 38% (5.72 g), respectively.
To 0.15 mol of 38% formalin solution, 0.15 mol of MDH was added in small quantities, stirring the reaction mixture in an ice bath for an hour (since the reaction is exothermic). Then, NaOH was added in small quantities until two layers were formed in the reaction mixture. Then, the water layer was separated from the organic layer. The organic layer was distilled with the provision of a rectification column at a temperature of 64 °C in case of MDH and under reduced pressure in case of MDEA. The desired products MDH and MDEA were colorless liquids.
Dimethylamine (DMA) was obtained according to the method [27] with a yield of 85% (2.46 g).
Into a 50 mL-two-necked flask was placed N,N-dimethylamine hydrochloride (5.3 g, 65.0 mmol) suspended in DCM (15 mL), and finely powdered KOH (10.0 g, 180.0 mmol, 2.7 equiv.) was slowly added in portions to hold the temperature between −15 and −5 °C. After the mixture was stirred for 1 h, filtration led to a colorless solution of N,N-dimethylamine.
1-(2-Oxocyclohexyl)ethane-1,1,2,2-tetracarbonitrile (1a), 1-(2-oxo-5-propylcyclohexyl)ethane-1,1,2,2-tetracarbonitrile (1b), 1-(1-methyl-2-oxohexyl-)ethane-1,1,2,2-tetracarbonitrile (1c), 1-(2-oxocyclododecyl)ethane-1,1,2,2-tetracarbonitrile (2) were obtained according to the general procedure [20] with the yields of 74% (0.20 g), 75% (0.27 g), 66% (0.20 g) and 61% (0.24 g), respectively.
Then, 1.25 mmol tetracyanoethylene (TCNE) in 5 mL of dioxane was added to 1.22 mmol of ketone 1a,b,c,2 in 5 mL of dioxane along with a catalytic amount of hydrochloric acid (1 drop). The progress of the process was determined via a test for hydroquinone (HQ), that forms a blue p-complex when reacting with TCNE. After the blue color ceased to appear, the dioxane solution was maintained at the temperature range of 0–5 °C in the freezer for 10 min. After this period of time, cold distilled water was added to the frozen reaction mixture in a volume equal to the dioxane solution. The reaction mixture was stirred until the precipitation. The desired product was separated by filtration through a Schott filter, followed by washing with cold distilled water.
Synthesis of 3-Amino-5-(dimethylamino)-1-oxo-4,5,6,7,8,9-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a,9b-dicarbonitrile (9a), 3-amino-5-(dimethylamino)-1-oxo-8-(propyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a,9b-dicarbonitrile (9b), 3-amino-5- (2-(dimethylamino)ethyl-1-oxo-4,5,6,7,8,9-hexahydro-1H-pyrrolo[3,4-c]quinoline-3a,9b-dicarbonitrile (9′), 2-(dimethylamino)-4a-methyl-10-oxo-5,6,7,8-tetrahydro-1H-8a,4-(epimino)quinoline-3,4(4aH)-dicarbonitrile (12c), (E)-2-amino-6,7,8,9,10,11,12,13-octahydro-5H-cyclododeca [b] pyran-3,4-dicarbonitrile (8).
The compounds were synthesized following a standard procedure, yielding 84% (0.21 g), 75% (0.18 g), 48% (0.12 g), 64% (0.14 g) and 62% (0.18 g), respectively. Initially, 8 mmol of TCEK in 5 mL of ethyl acetate was added to 8 mmol of MDH or MDEA, along with a catalytic amount of sodium hydroxide in 5 mL of ethyl acetate. The reaction progress was monitored using TLC, with N,N-dimethyl-N’-methylene hydrazine serving as the reference sample in terms of syntheses with TCEKs 1a,b,c, 2, MDEA, used as a reference sample in terms of synthesis with TCEK 1a. Then, 0.5–5 h later, sand-colored crystals precipitated. The desired product was separated by filtration through a Schott filter, followed by washing with cold ethyl acetate. Subsequently, recrystallization was performed using isopropanol as the solvent.
Synthesis of 2-(dimethylamino)-4a-methyl-10-oxo-5,6,7,8-tetrahydro-1H-8a,4-(epimino)quinoline-3,4(4aH)-dicarbonitrile (12c), (E)-2-amino-6,7,8,9,10,11,12,13-octahydro-5H-cyclododeca [b] pyran-3,4-dicarbonitrile (8) without MDH catalysis.
Firstly, 8 mmol of TCEK 2 was dissolved in 5 mL of ethyl acetate and allowed to react at room temperature for 24 h. Subsequently, the desired product precipitated out. The isolation and purification procedures were carried out following the same protocol as described above. The yield of the desired product was 54% (0.16 g).
In the specified quantities, the liberation of hydrogen cyanide does not present any danger. However, when dealing with larger quantities, it is imperative to utilize the aforementioned apparatus.
Synthesis of 5-Amino-1-(dimethylamino)-1,2-dihydro-3H-pyrrole-3,3,4-tricarbonitrile (12).
Firstly, 1.1 mmol of MDH was added to a solution of 1 mmol of TCNEH2 in 2 mL of ethyl acetate. The mixture was kept at room temperature for 14 h (TLC control) and cooled. Precipitate was filtered off and washed with 2 mL of cold ethyl acetate. Yield: 81%.

5. Conclusions

Thus, 1,1-dimethylhydrazine can engage in reactions with various structural elements:
–
Double bond (addition to the methylene-active position of tetracyanoketones via a Michael-type reaction);
–
Dimethylamine fragment (rearrangement in the 2-methylcyclohexanone derivative);
–
Labile hydrogen (addition to the double bond of tetracyanoethylene);
–
Serving as a catalyst (accelerating the cyclization of cyclohexanone into a pyran derivative).
This makes it an indispensable starting compound for the synthesis of various organic structures. It should be noted that the exceptional availability of this reagent is of great significance.

Supplementary Materials

The following supporting information can be downloaded at: https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/ijms241713076/s1.

Author Contributions

Conceptualization, O.E.N.; methodology, M.M.; formal analysis, E.I., A.E., D.G. and O.L.; investigation, M.M., V.A., M.O., T.V. and A.E.; resources, O.E.N.; data curation, O.L. and D.G.; writing—review and editing, O.E.N., E.I., M.O., T.V. and A.E.; visualization, E.I. and O.L.; supervision, O.E.N.; funding acquisition, O.E.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant number 23-23-00656.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Ulyanov Chuvash State University, Moskovsky pr., 15, Cheboksary 428015, Russia (protocol code XIX 7 March 2023).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Not applicable.

Acknowledgments

The authors gratefully acknowledge Russian Science Foundation number 23-23-00656 for support for this work.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kolesnikov, S.V. General Information about Fuel—1,1 Dimethylhydrazine, Oxidation of Asymmetric Dimethylhydrazine (Heptyl) and Identification of Its Transformation Products in Straits: Monograph; SibAK Publishing House: Novosibirsk, Russia, 2014; Volume K60, p. 110. ISBN 978-5-4379-0359-9. [Google Scholar]
  2. Klages, F.; Nober, G.; Kircher, F.; Bock, M. Untersuchungen in der Hydrazinreihe. I. Die Darstellung von Tri- und Tetra-alkyl-hydrazinen. Justus Liebig’s Ann. Chem. 1941, 547, 1–38. [Google Scholar] [CrossRef]
  3. Middleton, W.J.; Heckert, R.E.; Little, E.L.; Krespan, C.G. Cyanocarbon Chemistry. III.1Addition Reactions of Tetracyanoethylene. J. Am. Chem. Soc. 1958, 80, 2783–2788. [Google Scholar] [CrossRef]
  4. Fardis, M.; Jin, H.; Jabri, S.; Cai, R.Z.; Mish, M.; Tsiang, M.; Kim, C.U. Effect of substitution on novel tricyclic HIV-1 integrase inhibitors. Bioorganic Med. Chem. Lett. 2006, 16, 4031–4035. [Google Scholar] [CrossRef]
  5. Yamada, R.; Fukuda, K.; Kawanishi, M.; Ohmori, Y.; Nasu, M.; Seto, M.; Sasaki, Y.; Sunazuka, T.; Zhuorong, L.; Funato, N.; et al. Synthesis and activity of staurosporine analogs with a lactone functionality. Bioorganic Med. Chem. Lett. 1996, 6, 1893–1896. [Google Scholar] [CrossRef]
  6. Singh, S.B.; Goetz, M.A.; Jones, E.T.; Bills, G.F.; Giacobbe, R.A.; Herranz, L.; Stevens-Mile, S.; Williams, D.L. Oteromycin: A Novel Antagonist of Endothelin Receptor. J. Org. Chem. 1995, 60, 7040–7042. [Google Scholar] [CrossRef]
  7. Micheli, F.; Pasquarello, A.; Tedesco, G.; Hamprecht, D.; Bonanomi, G.; Checchia, A.; Jaxa-Chamiec, A.; Damiani, F.; Davalli, S.; Donati, D.; et al. Diaryl substituted pyrrolidinones and pyrrolones as 5-HT2C inhibitors: Synthesis and biological evaluation. Bioorganic Med. Chem. Lett. 2006, 16, 3906–3912. [Google Scholar] [CrossRef]
  8. Butora, G.; Morriello, G.J.; Kothandaraman, S.; Guiadeen, D.; Pasternak, A.; Parsons, W.H.; MacCoss, M.; Vicario, P.P.; Cascieri, M.A.; Yang, L. 4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties. Bioorganic Med. Chem. Lett. 2006, 16, 4715–4722. [Google Scholar] [CrossRef]
  9. Toja, E.; Gorini, C.; Zirotti, C.; Barzaghi, F.; Galliani, G. Amnesia-reversal activity of a series of 5-alkoxy-1-arylsulfonyl-2-pyrrolidinones. Eur. J. Med. Chem. 1991, 26, 403–413. [Google Scholar] [CrossRef]
  10. Luo, S.; Li, P.; Li, S.; Du, Z.; Hu, X.; Fu, Y.; Zhang, Z. N,N-Dimethyl Tertiary Amino Group Mediated Dual Pancreas- and Lung-Targeting Therapy against Acute Pancreatitis. Mol. Pharm. 2017, 14, 1771–1781. [Google Scholar] [CrossRef] [PubMed]
  11. Takács, D.; Egyed, O.; Drahos, L.; Szabó, P.; Jemnitz, K.; Szabó, M.; Veres, Z.; Visy, J.; Molnár, J.; Riedl, Z.; et al. Synthesis and pharmacological investigation of new N-hydroxyalkyl-2-aminophenothiazines exhibiting marked MDR inhibitory effect. Bioorganic Med. Chem. 2013, 21, 3760–3779. [Google Scholar] [CrossRef]
  12. Tompson, D.J. Steady-State Pharmacokinetic Properties of a 24-Hour Prolonged-Release Formulation of Ropinerole: Results of Two Randomized Studies in Patients with Parkinson’s Disease. Clin. Pharmacokinet. 2007, 29, 2654–2666. [Google Scholar] [CrossRef]
  13. Allnoch, L.; Peters, M.; Wiemer, F.; Wohlsein, P. Persistent bilateral mydriasis associated with pituitary adenoma in horses. J. Equine Vet. Med. 2020, 85, 102872. [Google Scholar] [CrossRef]
  14. Tatum, R.C.; McGowan, C.M.; Ireland, J.L. Efficacy of pergolide for the treatment of intermediate pituitary dysfunction in horses: A systematic review. Vet. J. 2020, 266, 105562. [Google Scholar] [CrossRef]
  15. Millan, M.J.; Maiofiss, L.; Cussac, D.; Audinot, V.; Boutin, J.A.; Newman-Tancredi, A. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharm. Exp. Ther. 2002, 303, 791–804. [Google Scholar] [CrossRef]
  16. Assion, H.J. (Ed.) Malignes Neuroleptisches Syndrom; Georg Thieme Verlag: New York, NY, USA, 2004; p. 33. ISBN 978-3-131-33171-7. [Google Scholar]
  17. Schmuck, K.; Ullmer, C.; Kalkman, H.O.; Probst, A.; Lubbert, H. Activation of meningeal 5-HT2B receptors: An early step in the generation of migraine headache? Eur. J. Neurosci. 1996, 8, 959–967. [Google Scholar] [CrossRef]
  18. Dressler, D. Apomorphin bei der Behandlung des Morbus Parkinson. Der Nervenarzt 2005, 76, 681–689. [Google Scholar] [CrossRef]
  19. Shih, S.-R.; Chen, S.-J.; Hakimelahi, G.H.; Liu, H.-J.; Tseng, C.-T.; Shia, K.-S. Selective human enterovirus and rhinovirus inhibitors: An overview of capsid-binding and protease-inhibiting molecules. Med. Res. Rev. 2004, 24, 449–474. [Google Scholar] [CrossRef] [PubMed]
  20. Dickinson, C.L. Cyanocarbon Chemistry. XV.1A New Synthesis of 3,4-Dicyano-2(1H)-pyridones. J. Am. Chem. Soc. 1960, 82, 4367–4369. [Google Scholar] [CrossRef]
  21. Fedoseev, S.V.; Ershov, O.V.; Belikov, M.Y.; Lipin, K.V.; Bardasov, I.N.; Nasakin, O.E.; Tafeenko, V.A. Domino synthesis of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-carbonitriles. Tetrahedron Lett. 2013, 54, 2143–2145. [Google Scholar] [CrossRef]
  22. Belikov, M.Y.; Ershov, O.V.; Eremkin, A.V.; Nasakin, O.E.; Tafeenko, V.A.; Nurieva, E.V. Reaction between 4-oxoalkane-1,1,2,2-tetracarbonitriles and morpholine: Regioselective synthesis of 5-amino-2-(morpholin-4-yl)-3-(2-oxoalkyl)-3H-pyrrol-3,4-dicarbonitriles. Tetrahedron Lett. 2011, 52, 6407–6410. [Google Scholar] [CrossRef]
  23. Dyachenko, V.D.; Rusanov, E.B. Isopropylidenemalononitrile in the synthesis of 2-amino-4,6,6-trimethylcyclohexa-2,4-diene-1,1,3-tricarbonitrile, 6-amino-2-(4-methoxybenzoylmethylsulfanyl)-4,4-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile, and fused 2-aminopyrans according to Michael. Russ. J. Org. Chem. 2006, 42, 1374–1379. [Google Scholar] [CrossRef]
  24. Dürr, U.; Kisch, H. In the Dark and in the Light: Homogeneous and Heterogeneous Catalytic Activation of 1,2-Diazenes. Synlett 2000, 12, 1335–1341. [Google Scholar] [CrossRef]
  25. Voelker, E.J.; Pleiss, M.G.; Moore, J.A. Heterocyclic studies. 33. 5-Methyl-6-phenyl-1,2-diazabicyclo[3.2.0]-2,6-heptadiene-4-one. Thermolysis to 4-methyl-5-phenylpyridazine. J. Org. Chem. 1970, 35, 3615–3619. [Google Scholar] [CrossRef]
  26. Moore, J.A.; Kwart, H.; Wheeler, G.; Bruner, H. Heterocyclic studies. XXIII. The cleavage of 2,3-dihydro-1,2-diazepin-4-ones with base. J. Org. Chem. 1967, 32, 1342–1346. [Google Scholar] [CrossRef]
  27. Banert, K.; Pester, T. Too Short-Lived or Not Existing Species: N-Azidoamines Reinvestigated. J. Org. Chem. 2019, 84, 4033–4039. [Google Scholar] [CrossRef]
  28. Hecht, S.M.; Werner, D.; Traficante, D.D.; Sundaralingam, M.; Prusiner, P.; Ito, T.; Sakurai, T. Structure determination of the N-methyl isomers of 5-amino-3,4-dicyanopyrazole and certain related pyrazolo[3,4-d]pyrimidines. J. Org. Chem. 1975, 40, 1815–1822. [Google Scholar] [CrossRef]
  29. Maryasov, M.A.; Davydova, V.V.; Nasakin, O.E.; Shteingolts, S.A.; Lodochnikova, O.A. Synthesis of 2,2-Dimethylhydrazonebut-2-enenitriles and [(2,2-Dimethylhydrazono)methyl]phenylacrylonitriles for Development of Antimicrobial Fluorescent Dyes. Gen. Chem. J. 2021, 91, 1613–1618. [Google Scholar] [CrossRef]
  30. Sheldrick, G.M. SHELXT: Integration of space group definition and structural solution. Act Crystallogr. 2015, 71, 3–8. [Google Scholar]
  31. Sheldrick, G.M. A Brief History of SHELX. Act Crystallogr. 2007, 64, 112–122. [Google Scholar] [CrossRef]
  32. Macrae, C.F.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Shields, G.P.; Taylor, R.R.; Tauler, M.; Van De Strick, J. Mercury: Visualization and analysis of crystal structures. J. Appl. Crystallogr. 2006, 39, 453–457. [Google Scholar] [CrossRef]
Ijms 24 13076 g001
Figure 1. Biologically active compounds containing the moiety of pyrrolidin-2-one.
Figure 1. Biologically active compounds containing the moiety of pyrrolidin-2-one.
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Figure 2. Structural analogs MDH, MDEA and DMDEA-containing biologically active compounds.
Figure 2. Structural analogs MDH, MDEA and DMDEA-containing biologically active compounds.
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Figure 3. Structural similarities in TCEKs derivatives and well-known drugs.
Figure 3. Structural similarities in TCEKs derivatives and well-known drugs.
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Figure 4. Structural similarities in cyclododecanone derivatives and flavanoids exhibiting antienteroviral activity.
Figure 4. Structural similarities in cyclododecanone derivatives and flavanoids exhibiting antienteroviral activity.
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Figure 5. MDH reaction centers.
Figure 5. MDH reaction centers.
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Figure 6. Reactions of cyclohexanone 1a, 4-propylcyclohexanone 1b, and 2-methylcyclohexanone 1c derivatives with MDH 1′a and cyclohexanone 1a with MDEA 1b’.
Figure 6. Reactions of cyclohexanone 1a, 4-propylcyclohexanone 1b, and 2-methylcyclohexanone 1c derivatives with MDH 1′a and cyclohexanone 1a with MDEA 1b’.
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Figure 7. Further chemical transformations of TCEK 1c.
Figure 7. Further chemical transformations of TCEK 1c.
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Figure 8. The crystal structure of 9a.
Figure 8. The crystal structure of 9a.
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Figure 9. The crystal structure of 9b.
Figure 9. The crystal structure of 9b.
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Figure 10. The crystal structure of 11c.
Figure 10. The crystal structure of 11c.
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Figure 11. Interaction between TCEK 2 and MDH.
Figure 11. Interaction between TCEK 2 and MDH.
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Figure 12. The crystal structure of 8.
Figure 12. The crystal structure of 8.
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Figure 13. Interaction between TCNE and MDH.
Figure 13. Interaction between TCNE and MDH.
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Figure 14. Interaction between TCNEH2 and MDH.
Figure 14. Interaction between TCNEH2 and MDH.
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Table 1. Yield, melting point, IR, MNR 1H, 13C and mass-spectra data.
Table 1. Yield, melting point, IR, MNR 1H, 13C and mass-spectra data.
Structural NumberYield, %Melting Point, °CIR (Nujol), νmax/cm−1MNR1Hδ, ppm, J, Hz (DMSO-d6)MNR 13C ppm, (DMSO-d6)HRMS(ESI) and Mass-Spectra, m/z
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9a		84217–2191659 (s) (C=C), 1736 (vs.) (C=O), 2241 (w) (C≡N), 3291 (vs., br) (NH2)9.63 (d, J = 30.32 Hz, 2H, NH2), 3.73 (d, J =11.67 Hz, 1H, CH24), 3.34 (d, J = 11.75 Hz, 1H, CH24), 2.33 (s, 6H, N(CH3)2), 2.28 (m, 2H, CH210), 2.24–2.10 (m, 2H, CH27), 1.65–1.54 (m, 2H, CH29), 1.53–1.29 (m, 2H, CH28).178.15 (C=O), 177.07 (C2), 144.94 (C6), 116.16 (C≡N21), 115.24 (C≡N16), 95.07 (C11), 59.76 (C3), 52.94 (C12), 51.08 (CH24), 39.52 (N(CH3)2), 24.92 (CH27), 24.55(CH28), 22.01 (CH29), 21.88 (CH210).[M + H]+ 299.1620 (calculated for [C15H19N6O]+—299.1620).
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9b		75214–2161640 (s) (C=C), 1745 (s) (C=O), 2251 (s) (C≡N), 3494 (vs., br) (NH2) 9.61 (d, J = 15.42 Hz, 2H, NH2), 3.96 (d, J =11.66 Hz, 1H, CH26), 3.20 (d, J = 11.63 Hz, 1H, CH26), 2.47 (m, 2H, CH210), 1.91 (t, J = 12.45 Hz, 2H, CH213), 1.72 (m, 2H, CH212), 1.49–1.42 (m, 2H, CH11), 1.38–1.28 (m, 2H, CH214), 1.28–1.17 (m, 2H, CH215), 1.04 (s, 3H, NCH317), 1.03 (s, 3H, NCH318), 0.88 (t, J = 7.01 Hz, 3H, CH3).178.07 (C=O), 177.15 (C5), 145.03 (C9), 116.19 (C≡N20), 115.30 (C≡N19), 94.70 (C8), 62.07 (C4), 53.33 (C3), 51.57 (CH26), 39.55 (N(CH3)217,18), 37.85 (CH6), 31.91(CH214, CH11), 28.41(CH213), 25.33 ((CH210,12)2), 19.63 (CH215), 14.18 (CH3).[M + H]+ 341.2090 (calculated for [C18H24N6O]+—341.2090).
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9′		62235–2361661 (s) (C=C), 1748 (vs.) (C=O), 2253 (w) (C≡N), 3291 (br), 3403 (w, br) (NH2)9.60 (s, 2H, NH2), 3.66–3.48 (dd, 2H, J = 12.88, 7.66 CH24), 3.25–3.00 (dh, 2H, J = 7.94, 1.88, CH218), 2.29 (dh, J = 6.60, 1.53 Hz, 2H, CH219), 2.18–2.15 (m, 4H, (CH27,10), 2 2.14 (s, 6H, N(CH3)2), 1.54 (m, 2H, CH28), 1.50 (m, 2H, CH29).179.31 (C=O), 177.80 (C2), 142.47 ((C11,6)2), 117.16 (C≡N23), 116.05 (C≡N16), 58.90 (CH219), 54.11 (C3), 51.78 (C12), 51.11 (C4), 47.74 (CH218), 46.24 (N(CH3)2), 25.94 (CH27), 25.78 (CH28), 22.93 (CH29), 22.70 (CH210).Gas-chromatography mass-spectrum: [M+H]+ 326 (calculated for [C17H22N6O]+—326.1933)
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12c		48>2501579 (s) (C=C), 1717 (vs) (C=O), 2168 (vs) (=C-C≡N), 2242 (w) (C≡N), 3167 (br), 3282 (w) (NH) 8.42 (s, 1H, NH1), 7.06 (s, 1H, NH6), 2.91 (s, 6H, N(CH3)2), 2.03–1.07 (m, 8H, (CH212−7)4), 0.89 (s, 3H, CH3)168.68 (C=O), 157.75 (C5), 120.99 (C≡N14), 115.88 (C≡N11), 71.98 (C5), 54.29 (C7), 51.62 (C12), 40.67 (C3), 40.09 (N(CH3)219,20), 31.86 (CH28), 26.66 (CH211), 20.86 (CH29), 20.06 (CH210), 13.72 (CH3).[M + H]+ 286.1668 (calculated for [C15H20N5O]+—286.1668)
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8		64210–2121547 (s) (C=C), 1658 (vs.) (C=C), 1731 (w) (=C-O), 2182 (s), 2233 (s) (C≡N), 3379 (w, br) (NH2)8.12 (s, 2H, NH2), 5.27 (t, J = 8.16 Hz, 1H, CH15), 2.20 (q, J = 6.15 Hz, 2H, CH214), 1.67–1.08 (m, 16H, (CH213−6)8).163.23 (C2), 145.43 (C16), 130.86 (C5), 116.93 (C4), 115.23 (CH15), 114.59 (C≡N20), 113.99 (C≡N18), 104.30 (C3), 28.33 (CH26), 27.93 (CH27), 27.53 (CH28), 26.72 (CH29), 26.43 (CH210), 26.20 (CH211), 25.85 (CH212), 25.66 (CH213), 25.09 (CH214).[M + H]+ 284.1763 (calculated for [C17H22N3O]+—284.1763)
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12		81163–1651646 (vs.) (C=C), 2112 (vs.), 2165 (s) (C≡N), 3177 (w, br), 3240 (w, br), 3362 (w, br), 3386 (w, br) (NH2)7.56 (s, 2H, NH2),
4.05 (s, 2H, CH25),
2.43 (s, 6H, N(CH3)2).		161.85 (C3), 117.70 (C≡N9), 115.14 ((C≡N11,10)2), 48.42 (CH25), 46.42 (C2), 42.24 (N(CH3)2), 34.59 (C1)[M + H]+ 203.1047 (calculated for [C9H10N6]+—203.1045)
Table 2. Crystal data and structure refinement for 9a, 9b, 12c and 8.
Table 2. Crystal data and structure refinement for 9a, 9b, 12c and 8.
Identification Code9a9b12c8
Empirical formulaC15H18N6O C22H32N6O3C15H19N5O C17H21N3O
Formula weight298.35 428.53 285.35 283.37
Temperature/K104(7) 102.2(9) 100(1) 99.9(10)
Crystal systemtriclinic triclinic triclinic triclinic
Space groupP-1 P-1 P-1 P-1
a/Å13.9756(12) 9.42370(10) 7.5867(2) 8.5574(5)
b/Å15.0773(15) 11.97650(10) 9.1339(3) 9.7008(6)
c/Å18.0923(13) 11.99720(10) 10.8470(4) 9.7930(4)
α/°112.010(8) 111.2460(10) 76.621(3) 102.032(4)
β/°93.942(7) 111.1820(10) 82.305(3) 103.106(4)
γ/°112.380(9) 93.9690(10) 81.452(3) 101.505(5)
Volume/Å33167.3(5) 1145.11(2) 719.26(4) 747.97(7)
Z8 2 2 2
ρcalcmg/mm31.251 1.243 1.318 1.258
μ/mm−10.683 0.690 0.703 0.632
F(000)1264.0 460.0 304.0 304.0
Crystal size/mm30.18 × 0.08 × 0.02 0.208 × 0.191 × 0.123 0.1 × 0.05 × 0.04 0.15 × 0.1 × 0.04
2Θ range for data collection5.436 to 156.656°8.14 to 153.026° 8.424 to 152.906° 9.618 to 153.2°
Index ranges−17 ≤ h ≤ 17, −18 ≤ k ≤ 18, −15 ≤ l ≤ 22 −10 ≤ h ≤ 11, −14 ≤ k ≤ 14, −15 ≤ l ≤ 14 −9 ≤ h ≤ 8, −11 ≤ k ≤ 11, −12 ≤ l ≤ 13 −10 ≤ h ≤ 10, −12 ≤ k ≤ 12, −11 ≤ l ≤ 12
Reflections collected34,121 33,743 17,589 7141
Independent reflections12,415 [R(int) = 0.1673] 4548 [R(int) = 0.0349] 2865 [R(int) = 0.0345] 2981 [R(int) = 0.0614]
Data/restraints/parameters12,415/0/801 4548/45/302 2865/0/193 2981/0/190
Goodness-of-fit on F21.003 1.034 1.021 1.090
Final R indexes [I ≥ 2σ (I)]R1 = 0.0845, wR2 = 0.1731 R1 = 0.0422, wR2 = 0.1082 R1 = 0.0399, wR2 = 0.0966 R1 = 0.0821, wR2 = 0.2250
CCDC numbers2,152,2622,152,2632,152,2642,152,265
Table 3. Substituents R1, R2, R3 and original compounds 1′a,b and 1a–c.
Table 3. Substituents R1, R2, R3 and original compounds 1′a,b and 1a–c.
1–9a1–9b1–6c2′–9′
R1Ijms 24 13076 i007Ijms 24 13076 i008Ijms 24 13076 i007Ijms 24 13076 i007
R2Ijms 24 13076 i007Ijms 24 13076 i007Ijms 24 13076 i009Ijms 24 13076 i007
R3Ijms 24 13076 i010Ijms 24 13076 i010Ijms 24 13076 i010Ijms 24 13076 i011
1′aaab
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Ivanova, E.; Maryasov, M.; Andreeva, V.; Osipova, M.; Vasilieva, T.; Eremkin, A.; Lodochnikova, O.; Grishaev, D.; Nasakin, O.E. Treatment of Substandard Rocket Fuel 1,1-Dimethylhydrazine via Its Methylene Derivative into Heterocycles Based on Pyrrolo-[3,4c]Quinolines, Cyclododeca[b]piran and Pyrrole. Int. J. Mol. Sci. 2023, 24, 13076. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713076

AMA Style

Ivanova E, Maryasov M, Andreeva V, Osipova M, Vasilieva T, Eremkin A, Lodochnikova O, Grishaev D, Nasakin OE. Treatment of Substandard Rocket Fuel 1,1-Dimethylhydrazine via Its Methylene Derivative into Heterocycles Based on Pyrrolo-[3,4c]Quinolines, Cyclododeca[b]piran and Pyrrole. International Journal of Molecular Sciences. 2023; 24(17):13076. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713076

Chicago/Turabian Style

Ivanova, Elizaveta, Maxim Maryasov, Vera Andreeva, Margarita Osipova, Tatyana Vasilieva, Alexey Eremkin, Olga Lodochnikova, Denis Grishaev, and Oleg E. Nasakin. 2023. "Treatment of Substandard Rocket Fuel 1,1-Dimethylhydrazine via Its Methylene Derivative into Heterocycles Based on Pyrrolo-[3,4c]Quinolines, Cyclododeca[b]piran and Pyrrole" International Journal of Molecular Sciences 24, no. 17: 13076. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713076

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