Derivatives of the triaminoguanidinium ion, 6. Aminal-forming reactions with aldehydes and ketones

Jan Szabo
  • Institute of Organic Chemistry I, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
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and Gerhard Maas
  • Corresponding author
  • Institute of Organic Chemistry I, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
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Abstract

Cyclic aminals (N,N-acetals) could be prepared by the reaction of N,N′,N″-triaminoguanidinium sulfate, N,N′,N″-tris(benzylamino)guanidinium chloride or N,N′,N″-tris(benzylamino)guanidine with formaldehyde or acetone. In all cases, 1,2,4,5-tetrazinane derivatives were obtained, which were structurally confirmed by X-ray crystal structure determinations. In two cases, 1:1 cocrystals of two different tetrazinane products were isolated. On the other hand, the reaction of N,N′,N″-tris(benzylamino)guanidinium chloride with benzaldehyde yielded a 3-(2-benzylidenehydrazin-1-yl)-1H-1,2,4-triazole.

1 Introduction

N,N′,N″-Triaminoguanidinium salts 1 (Fig. 1) are readily accessible, simple building blocks for organic synthesis, which due to their C3-symmetric topology and functional group presence offer diverse opportunities for the preparation of other ionic or neutral guanidine derivatives and of nitrogen heterocycles [1], [2]. By reaction with aldehydes or ketones, the three NH2 groups in 1 allow the straightforward conversion into tris(imines) (or (tris(hydrazones)) 2 [2], [3], [4], [5], [6], some of which were employed as ligands with multiple coordination sites in transition metal complexes showing remarkable three-dimensional architectures [2], [5], [7], [8].

N,N′,N″-Tris(benzylidenamino)guanidinium salts 3 are easily prepared by catalytic C=N hydrogenation of tris(benzylidenimino)guanidinium salts 2 (R1=Ph, R2=H) [9]. Some years ago, we started to study the chemistry of salts 3, which in particular were expected to undergo multiple functionalization based on the nucleophilicity of the benzyl-NH nitrogen atom. Thus, 3-Cl was found to undergo threefold N-carbamoylation with various arylisocyanates and thiocarbamoylation (leading to thiourea derivatives) with arylisothiocyanates [10]. In a similar manner, triple N-acylation with acid chlorides produced N,N′,N″-tris(N-acyl-N-benzylamino)guanidines, which under the action of aqueous NaOH could be transformed into mesoionic 1,2,4-triazolium-3-aminides [11]. Reactions of salts 3 with aldehydes or ketones have not been reported so far.

The presence of three amino groups in the cations of salts 1–3 suggests, that cyclic aminals (N,N-acetals) could result from their reactions with aldehydes or ketones. We report in this paper on so far unknown aminal forming reactions using formaldehyde, benzaldehyde and acetone as the carbonyl component.

2 Results and discussion

2.1 Reaction of the triaminoguanidinium ion with acetone

In an earlier paper, we have reported the synthesis of N,N′,N″-tris(propan-2-iminyl)guanidine 4 from 1 (X=Cl) and acetone [6]. A threefold condensation reaction probably gave rise to guanidinium salt 2, which, however, was not isolated as a pure product. Rather, the solid residue obtained after evaporation of the solvent was treated with aqueous NaOH to furnish the neutral guanidine 4 (Scheme 1). We report now, that under modified conditions two novel species could be isolated, which are likely intermediates in the conversion of triaminoguanidinium ion 1 into N,N′,N″-tris(propan-2-ylidenamino)guanidinium ion 2. To this end, an anion exchange 1-Cl1-SO4 was performed by passing an aqueous solution of the former over an ion-exchange resin loaded with sulfate ions. When the aqueous solution of 1-SO4 was exposed to acetone vapor, a crystalline precipitate was formed which was identified as the double salt (5a, 5b) SO4·2H2O (30% yield after 3 days) by an X-ray crystal structure determination (Fig. 2). We assume that a network of hydrogen bonds between NH groups, sulfate ions and water molecules accounts for the low solubility in the water-acetone reaction medium.

Scheme 1:
Scheme 1:

Reaction of the N,N′,N″-triaminoguanidinium ion 1 with acetone. aAcetone as solvent, 4 days, r.t.; see ref. [6].

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

Fig. 1:
Fig. 1:

N,N′,N″-Triaminoguanidinium salts 1 and derivatives thereof.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

Fig. 2:
Fig. 2:

Solid-state structure of the co-crystal of 5a (lower part of picture) and 5b with one SO42− anion and two H2O molecules in the asymmetric unit (Mercury). Hydrogen bonds are shown as blue-violet dashed bonds. N–H⋯O hydrogen bonds connect both cations with sulfate anions (one of the two SO42− ions shown does not belong to the asymmetric unit), and O–H⋯O hydrogen bonds between sulfate anions and water molecules are also present. For the sake of clarity, not all short intermolecular contacts are shown. Selected bond lengths in 5a (Å): C1–N1 1.322, C1–N3 1.323, C1–N5 1.348, N1–N2 1.426, N3–N4 1.425, N5–N6 1.417, C2–N2 1.480, C2–N4 1.479. Selected bond lengths in 5b (Å): C5–N7 1.322, C5–N9 1.336, C5–N11 1.342, N11–N12 1.390, N7–N8 1.417, C6–N8 1.479, C6–N10 1.477, N10–N9 1.428(3); all estimated standard deviations are at ±0.003 Å.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

Evidently, the two 2,3,4,5-tetrahydro-1,2,4,5-tetrazin-1-ium ions 5a and 5b result from a cyclic aminal (N,N-acetal) formation involving two branches of 1 and the carbonyl compound. This process is similar to the formation of five- or six-membered cyclic aminals from secondary 1,n-diamines (n=1, 2) and aldehydes [12], [13], [14] or ketones [13], [14] in aqueous reaction media. These preparations have been shown to be equilibrium reactions [13], [14]. Moreover, evidence for the reversibility of the aminal synthesis from imines and primary amines comes from transimination reactions in organic solvents [15]. By analogy it was not unexpected that further exposure of isolated (5a, 5b)SO4·2H2O followed by deprotonation with aqueous NaOH furnished the neutral guanidine derivative 4, which was identified by its 1H and 13C NMR signals (see ref. [6]).

2.2 Reaction of the N,N′,N″-tris(benzylamino) guanidinium ion with aldehydes

The reaction of N,N′,N″-tris(benzylamino)guanidinium salt 3-Cl with paraformaldehyde under acidic conditions furnished the symmetrically tetrasubstituted 1,2,4,5-tetrazinane 6 in moderate yield (Scheme 2). The molecular structure was confirmed by an XRD analysis, which revealed a centrosymmetric chair conformation of the tetrazinane ring with axial benzyl substituents and trans-positioned vicinal triazole rings (Fig. 3); for a tetrazinane with analogous conformation, see ref. [16].

Scheme 2:
Scheme 2:

Reaction of tris(benzylamino)guanidinium salt 3-Cl with aldehydes.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

Fig. 3:
Fig. 3:

Solid-state structure of 6 (Ortep). The molecule has a crystallographic inversion center. Torsion angle C11–N2–N1i–C2i 135.95°.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

In contrast to formaldehyde, the reaction of benzaldehyde with 3-Cl required harsher conditions and only the 3-(2-benzylidenehydrazin-1-yl)-1H-1,2,4-triazole 7 was finally isolated in modest yield (Scheme 2). An XRD structure determination (Fig. 4) revealed the identity of 7 and also showed, that in the crystal structure centrosymmetric dimers are present, which are held together by two N–H⋯N hydrogen bridges. A hydrogen-bonded eight-membered ring motif is thus created (graph set R22(8) [17]). The 3-amino-1H-1,2,4-triazole moiety H–Namino–C=N is isostructural to a COOH group, and analogous homo-dimers are often found in solid-state structures of carboxylic acids; furthermore, the same hydrogen bond pattern occurs in several 3-amino-1,2,4-triazolium carboxylate complexes [18]. In the crystal structure of the parent 3-amino-1H-1,2,4-triazole, on the other hand, all nitrogen atoms are involved in a network of hydrogen bonds, but centrosymmetrical eight-membered cyclic dimers as in 7 are not present [19].

Fig. 4:
Fig. 4:

Solid-state structure of 7 (Mercury). A centrosymmetric dimer is shown, which is maintained by two N–H⋯N hydrogen bonds [distances (Å): N2⋯N4 3.042(2), N4–H 0.89(2), N2⋯H(N4) 2.19(2); angle N2⋯H–N4 159.3(16)°].

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

A mechanistic proposal for the reaction of triaminoguanidinium salt 3-Cl with formaldehyde (generated in situ from paraformaldehyde) or benzaldehyde is presented in Scheme 3. It is based on the assumption that 4-hydrazinyl-1,2,4-triazoles 9 (R=H or Ph) are the key intermediates, which are formed by condensation of the aldehyde with one of the nucleophilic benzylamine nitrogen atoms, 1,5-cyclization to an N-protonated triazolidine, and deprotonation as well as β-elimination of benzylamine. In the presence of formaldehyde, the benzylhydrazine side-chain of 9 is transformed into an azomethine imine dipole 8 which can dimerize in a formal (3+3) cycloaddition to furnish 1,2,4,5-tetrazinane 6. The formation of symmetrically substituted 1,2,4,5-tetrazinanes from hydrazine [20] or substituted hydrazines [16], [21], [22] and aldehydes or ketones is known. Starting from N1-alkyl-N2-acylhydrazines, the azomethine imine intermediate has been trapped in 1,3-dipolar cycloaddition reactions [21], [22]. In the presence of benzaldehyde, 3-Cl does not appear to react in the same manner; instead, a spontaneous benzylamine → benzylimine dehydrogenation could generate hydrazone 7.

Scheme 3:
Scheme 3:

Proposed mechanism of the reaction of 3-Cl with aldehydes.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

2.3 Reaction of N,N′,N″-tris(benzylamino)guanidine with acetone

N,N′,N″-Tris(benzylamino)guanidine (10) is readily obtained by base-assisted deprotonation of guanidinium salt 3-Cl with aqueous NaOH (Scheme 4). We noticed, however, that the aqueous solution of 3-Cl instantanously developed a yellow color on contact with the base and turned orange on prolonged standing. Control experiments showed this phenomenon to occur only in the presence of air and also with amine bases instead of NaOH. NMR monitoring revealed that a stepwise dehydrogenation of the three PhCH2–NH groups of 10 took place, which finally resulted in tris(benzylidenamino)guanidine 13. The latter can be obtained more conveniently by deprotonation of N,N′,N″-tris(benzylidenamino)guanidinium chloride 14 (which is in fact the direct synthetic precursor of 3-Cl [9]). A crystal structure determination confirmed the identity of 13 (Fig. 5).

Scheme 4:
Scheme 4:

Formation and stepwise dehydrogenation of N,N′,N″-tris(benzylamino)guanidine 10 in basic medium. a=exposure to air.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

Fig. 5:
Fig. 5:

Solid-state molecular structure of 13 (Ortep). Bond distances (Å): C1–N1 1.356(3), C1–N2 1.329(3), C1–N3 1.343(3), N1–N4 1.371(2), N2–N5 1.406(3), N3–N6 1.388(3), N4–C2 1.277(3), N5–C3 1.260(3), N6–C4 1.299(3).

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

The progress of the dehydrogenation cascade was monitored by 1NMR spectroscopy (Table 1). It can be seen, that under the given reaction conditions the first step (1011) has an appromixate half-life time of 1 h, whereas the reaction mixture contains 11 and 12 in the ratio 14:86 after 72 h. The last step (1213) appears to be rather slow, and only a small amount of 13 (9%) was observed after 90 h. The spontaneous dehydrogenation of the benzylamino groups in 10–12 is remarkable. In other cases, the conversion of a benzylhydrazine into a benzylhydrazone with oxygen was achieved in the presence of transition-metal catalysts (N-methyl-N-phenyl-N′-benzylhydrazine, air, Ru(bpyrz)2+, hν [23]; benzyl 2-benzylhydrazinecarboxylate, O2, Cu(OAc)2 [24]).

Table 1:

Progress of the stepwise dehydrogenation of N,N′,N″-tris(benzylidenamino)guanidine 10a.

Reaction time (h)10 (%)11 (%)12 (%)13 (%)
15050
4207010
721486
904879

aConditions: solution of 3-Cl in (CD3)2SO, addition of aqueous NaOH (5 m), then stirring the air-saturated solution at room temperature. Relative percentage values as determined by 1H NMR integration are given. See experimental section for NMR data.

A remarkable feature in the molecular structure of guanidine 13 (Fig. 5) is worth being mentioned. The C–N bond lengths in the CN3H2 core are rather similar, the imine bond C–N2 bond (1.329 Å) being distinctly longer than a typical C=N double bond and the two C–NH single bonds (1.343 and 1.356 Å) being shorter than expected (for a comparison, see the bond distances in the guanidine moiety of 16, Fig. 6). This kind of bond length equalization may be due to extended π (cross-)conjugation, which includes the two n orbitals of the NH nitrogen atoms. A positional disorder, caused by 120° rotations around the axis perpendicular to the CN3 plane, which would mimic a C3-symmetric molecule, appears less likely, as no residual electron density in a reasonable geometry that would suggest the presence of a hydrogen atom bonded at N2 was found. On the other hand, NMR spectra of 13 in (CD3)2SO (DMSO-d6) are temperature-dependent: spectra taken at T=298 K point to a static strucure with three magnetically different branches of the molecule, in contrast to a time-averaged C3-symmetric structure at 353 K (see Section 4.5). As we have discussed for N,N′,N″-tris(propan-2-iminyl)guanidine [6], prototropic tautomerism in the CN3H2 core is likely to be the dominant dynamic process.

Fig. 6:
Fig. 6:

Molecules 15 (left) and 16 in the 1:1 cocrystal (Ortep). Bond distances (Å) in 15: C1–N1 1.287(2), C1–N3 1.372(2), C1–N5 1.389(2), N5–N6 1.374(2), N6–C19 1.283(2), N1–N2 1.434(2), N3–N4 1.425(2). Bond distances (Å) in 16: C28–N7 1.394(2), C28–N9 1.366(2), C28–N12 1.285(2), N7–N8 1.452(2), N9–N10 1.430(2), N11–N12 1.451(2). Intermolecular hydrogen bonds between 15/15 and 15/16 [d(N–H)/d(H⋯N)/d(N⋯N)/<(N–H⋯N)]: N3–H⋯N4 (−x, −y+1, −z) 0.86 Å/2.42 Å/3.216 Å/155°; N5–H⋯N11 0.99/2.21/3.202/175; N5–H⋯N12 0.99/2.69/3.544/145; N7–H⋯N12 (−x, −y+1, −z+1) 0.87/2.24/3.106/172; N10–H⋯N1) 0.92/2.18/3.059/159.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

To explore the reactivity of tris(benzylamino)guanidine 10 and its dehydrogenated descendants toward acetone, the procedure indicated in Scheme 5 was applied. Deprotonation of guanidinium salt 3-Cl generated guanidine 10, which was exposed to air for 1 h, then dissolved in acetone. Addition of pentane by the vapor diffusion method provided crystals, which were identified as 1:1 cocrystals of 1,2,3,4-tetrahydro-1,2,4,5-tetrazine 15 and 2H,3H,4H,6H,7H,8H-[1,2,3]triazolo[4,3-b][1,2,4,5]tetrazine 16 (Fig. 6). (For a synthesis of the fully unsaturated parent system, see ref. [25]). The two compounds, which were obtained in 56% combined yield, could not be separated by liquid chromatography. Taking into account the aforementioned observations concerning the stepwise aerobic dehydrogenation of guanidine 10, we suggest that both guanidines 10 and 11 are involved in the reaction. Acetone could react with 10 to form an aminal 17, which after dehydrogenation of the PhCH2–NH group would deliver tetrazinane 15. On the other hand, formation of a cyclic five-membered aminal 18 could be formed from 11 and acetone, and a subsequent intramolecular amine-to-imine aminal formation would provide the bicyclic tetrazine derivative 16. As the sequence of individual steps (dehydrogenation vs. aminal formation) may be interchanged, modified reaction pathways cannot be excluded (nor the possibility that both products come from the same precursor, guanidine 10 or 11).

Scheme 5:
Scheme 5:

Synthesis of tetrazinane derivatives 15 and 16 and a mechanistic proposal.

Citation: Zeitschrift für Naturforschung B 75, 3; 10.1515/znb-2019-0216

Figure 6 shows molecules of 15 and 16 in the cocrystal. As one would expect, the C=N double bond in the guanidine moieties of both molecules is distinctly shorter [C–N1 1.287(2), C28–N12 1.285(2) Å] than the C–N single bonds (1.366–1.394 Å). This excludes the presence of an NH tautomer with an exocyclic C=N bond, in contrast to the situation in guanidine 13. In the crystal structure, molecules of 15 and 16 are connected by several N–H···N hydrogen bonds; one of them is found between two molecules of 15, the other ones between molecules of 15 and 16.

3 Conclusion

We have shown that the formation of six- and five-membered cyclic aminals is a straightforward step in the reaction of triaminoguanidinium salts, tris(benzylamino)guanidinium chloride or tris(benzylamino)guanidine with aldehydes or ketones. Some of these aminals could be isolated, others are likely reaction intermediates. The formed six-membered cyclic aminals (1,2,4,5-tetrazine derivatives 5a, 5b, 6, 15) offer interesting perspectives, since the successful conversion ot the 5a/5b mixture with acetone into N,N′,N″-tris(propan-2-iminyl)guanidine 4 (see Scheme 1) suggests that an analogous reaction with other carbonyl compounds could lead to so far unknown unsymmetrically substituted triaminoguanidine derivatives. Furthermore it should be recalled, that certain 1,2,4,5-tetrazinanes were found to have useful analgesic and antiinflammatory activities [26] and some dihydrotetrazine derivatives [27], in contrast to substituted 1,2,4,5-tetrazinanes [28], exhibited strong antitumor effects.

4 Experimental section

4.1 General information

NMR spectra were recorded on Bruker Avance 400 (1H: 400.13 MHz; 13C: 100.62 MHz) and Avance 500 spectrometers (1H: 500.14 MHz, 13C: 125.76 MHz). The signal of the solvent was used as an internal standard: δH((CH3)2SO)=2.50 ppm, δC((CD3)2SO)=39.43 ppm. NMR spectra were measured at T=298±2 K, if not stated otherwise. IR spectra: Bruker Vector 22; wavenumbers (cm−1) and intensities (vs=very strong, s=strong, m=medium, w=weak, br=broad) are given. Elemental analyses: elementar vario MICRO cube. Melting points were determined with a Büchi Melting Point B-540 apparatus; the heating rate was 3 K min−1. The reactions were carried out under air atmosphere if not stated otherwise.

Guanidinium salts 1-Cl [29], 3 [9] and 14 [9] were prepared as reported.

4.2 (6-(Hydrazin-1-yl)-3,3-dimethyl-2,3,4, 5-tetrahydro-1,2,4,5-tetrazin-1-ium (5a) and 3,3-dimethyl-6-(2-propan-2-ylidene)hydrazin-1-yl)-2,3,4,5-tetrahydro-1,2,4,5-tetrazin-1-ium (5b) sulfate (1:1 cocrystal) (5a·5b·SO4)

A chromatographic column (l=50 cm, diameter 5 cm) was charged with a strongly basic anion exchanger (type III, OH form, Merck Supelco, 4.0 g) dispersed in water (50 mL). An anion exchange was achieved by passing a saturated aqueous solution of sodium sulfate (40 mL) through the column, followed by an aqueous wash (10 mL) and elution with a solution of N,N′,N″-triaminoguanidinium chloride (1-Cl, 2.00 g, 14.22 mmol) in water (5 mL). Slow addition of acetone to the slightly orange-colored eluate by vapor diffusion led to a deeper coloration and colorless crystals of (5a, 5b)SO4·2H2O appeared, which were isolated by filtration. A suitable crystal was used for X-ray diffraction. Freeze-drying of this batch afforded 921 mg (2.16 mmol, 30%) of the anhydrous double salt (5a, 5b)SO4 as a microcrystalline solid; m. p. 180°C (dec.). – 1H NMR ((CD3)2SO, 500.14 MHz): δ=1.12 (s, 6 H, C(CH3)2), 1.14 (s, 6 H, C(CH3)2), 1.90 (s, 6 H, N=C(CH3)2), 3.60–6.1 (broad unstructured signals with maximum intensities at 4.45 and 5.32 ppm, 8 H, NHtetrazine + NH2), 7.70–10.50 (region of coalescing signals) ppm. – 13C NMR ((CD3)2SO, 125.76 MHz): δ=17.98 (N=C(CH3)2), 22.42 (C(CH3)2) 22.49 (C(CH3)2), 24.84 (N=C(CH3)2), 62.29 (C(CH3)2), 64.50 (C(CH3)2), 150.02 ((CN3)+), 152.96 (N=C(CH3)2), 153.15 ((CN3)+) ppm. – IR (KBr): ν=3700–2800 (very broad, strong maximum at 3211), 1676 (s), 1626 (vs), 1440 (m), 1378 (m), 1335 (m), 1266 (m), 1241 (m), 1115 (vs), 981 (m), 821 (m), 619 (s) cm−1. – Anal. for (C4H13N6)+×(C7H17N6)+×SO42− (C11H30N12O4S, 426.50 g mol−1): calcd. C 30.98, H 7.09, N 39.41, S 7.52; found C 30.77, H 6.93, N 39.59, S 7.39.

4.3 1,4-Dibenzyl-2,5-bis(1-benzyl-1H-1,2,4-triazol-3-yl)-1,2,4,5-tetrazinane (6)

N,N′,N″-Tris(benzylamino)guanidinium chloride (3-Cl) (1.64 g, 4.00 mmol) was dissolved in chloroform (30 mL) and paraformaldehyde (360 mg, corresponding to 12.00 mmol formaldehyde) suspended in methanol (15 mL) as well as hydrochloric acid (2 m, 2 mL) were added. The stirred mixture was heated at reflux for 2 h, a clear solution being formed already after 10 min. The solution was allowed to assume room temperature and stirred for additional 16 h, then concentrated as far as it remained clear. On exposure to an ether atmosphere overnight, colorless crystals separated, which were isolated by filtration, washed with Et2O, and re-dissolved in hot MeOH–acetone (3:1 v/v). The product was precipitated by addition of water, filtered off, and freeze-dried. Yield: 984 mg (1.60 mmol, 42%); m.p. 190.9–191.4°C. – 1H NMR ((CD3)2SO, 500.14 MHz): δ=3.98 (s, 4 H, CH2N–CH2Ph), 4.69 (broad s, 4 H, NCH2N), 5.30 (s, 4 H, Ntriazole–CH2Ph), 7.17–7.19 (m, 6 H, HPh), 7.30–7.40 (m, 14 H, HPh), 8.38 (s, 2 H, N=CH) ppm. – 13C NMR ((CD3)2SO, 125.76 MHz): δ=52.05 (NtriazoleCH2Ph), 53.41 (CH2N–CH2Ph), 57.58 (NCH2N); 126.87, 127.62, 127.74, 127.83, 128.53, 128.68 (all CHPh); 136.78 (i-CPh), 137.96 (i-CPh), 143.79 (N=CH), 165.12 (N=C) ppm. – IR (KBr): ν=3511 (m), 3029 (m), 2933 (m), 2858 (m), 1634 (s), 1550 (vs), 1494 (s), 1452 (s), 1370 (m), 1318 (m), 1209 (m), 1154 (m), 1069 (m), 1024 (s), 801 (m), 742 (s) cm−1. – Anal. calcd. for C34H34N10 (582.72 g mol−1): C 70.08, H 5.88, N 24.04; found C 69.73, H 5.97, N 24.22.

4.4 1-Benzyl-3-(2-((E)-benzylidene)hydrazin-1-yl)-5-phenyl-1H-1,2,4-triazole (7)

A stirred solution of N,N′,N″-tris(benzylamino)guanidinium chloride (3-Cl) (2.05 g, 5.00 mmol) and benzaldehyde (1.1 mL, 10.88 mmol) in chloroform (50 mL) was heated at 50°C for 67 h. The solution turned green and benzylammonium chloride precipitated, which was filtered off and washed with CHCl3. The combined filtrates were placed in a separatory funnel and washed with water (50 mL) and hydrochloric acid (1 m, 2 mL) to remove any benzylamine. The organic phase was separated, dried (MgSO4), and the residue obtained after solvent evaporation was submitted to a flash chromatography over silica gel (eluent ethyl acetate, Rf=0.7–1.0). The obtained product was dried at 0.05 mbar to yield a beige-colored solid. Yield: 597 mg (1.69 mmol, 34%); m. p. 170.9–171.9°C. – 1H NMR ((CD3)2SO, 400.13 MHz): δ=5.40 (s, 2 H, CH2), 7.16 (d, J=7.1 Hz, 2 H, HPh), 7.28–7.38 (m, 6 H, HPh), 7.52–7.54 (m, 2 H, HPh), 7.59–7.61 (m, 3 H, HPh), 7.65–7.68 (m, 2 H, HPh), 8.02 (s, 1 H, N=CH), 10.83 (s, 1 H, NH) ppm. – 13C NMR ((CD3)2SO, 100.61 MHz): δ=51.91 (CH2); 125.91, 126.67, 127.60, 127.79, 128.30, 128.36, 128.65, 128.74, 128.98, 130.11 (all CHPh); 135.42 (CPh), 136.80 (CH2CPh), 139.31 (N=CHPh), 153.61 (C-5triaz), 160.98 (C-3triaz) ppm. – IR (KBr): ν=3197 (s), 3034 (s), 1737 (m), 1569 (s), 1532 (s), 1471 (s), 1450 (s), 1416 (m), 1363 (s), 1322 (s), 1300 (s), 1247 (m), 1222 (m), 1158 (m), 1123 (s), 1061 (m), 1029 (m), 1013 (m), 930 (m), 752 (s), 721 (s), 695 (s) cm−1. – Anal. calcd. for C22H19N5 (353.43 g mol−1): C 74.77, H 5.42, N 19.82; found C 74.67, H 5.44, N 19.72.

4.5 N,N′,N″-Tris(benzylidenamino)guanidine (13)

To a solution of N,N′,N″-tris(benzylidenamino)guanidinium chloride (14, 1.76 g. 4.37 mmol) [9] in methanol (40 mL) was gradually added an aqueous solution of NaOH (5 m, 10 mL). After stirring during 1 h at ambient temperature, the precipitate was filtered off, washed with diethylether and water and dried at 130°C/0.05 mbar) to furnish 1.38 g (3.75 mmol, 86%) of a yellow solid. M. p. 199.0–200.0°C. – 1H NMR ((CD3)2SO, 400.13 MHz): δ=7.41–7.48 (m, 9 H, HPh), 7.70 (d, J=7.2 Hz, 2 H, o-HPh), 7.86 (d, J=7.2 Hz, 2 H, o-HPh), 7.91 (d, J=6.8 Hz, 2 H, o-HPh), 8.34 (s, 1 H, N=CH), 8.40 (s, 1 H, N=CH), 8.47 (s, 1 H, N=CH), 10.22 (s, 1 H, NH), 10.59 (s, 1 H, NH) ppm. – 1H NMR ((CD3)2SO, 500.16 MHz, T=353 K, fast exchange region): δ=7.38–7.45 (m, 9 H, HPh), 7.81 (d, J=7.1 Hz, 6 H, o-HPh), 8.41 (s, 3 H, N=CH), 10.21 (br. s, 2 H, NH) ppm. – 13C NMR ((CD3)2SO, 125.76 MHz, T=353 K): δ=126.67, 128.23, 128.80 (two CPh signals probably coincide at 128.23), 135.00 (N=CH), 151.50 (CN,N,N) ppm. – IR (KBr): ν=3320 (m), 3056 (w), 3022 (w), 1625 (s), 1580 (s), 1538 (s), 1487 (s), 1447 (s), 1429 (s), 1351 (m), 1286 (m), 1226 (m), 1136 (s), 1092 (s), 1069 (m), 940 (m), 758 (s), 694 (s) cm−1. – Anal. calcd. for C22H20N6 (368.44 g mol−1): C 71.72, H 5.47, N 22.81; found C 71.95, H 5.47, N 22.74.

4.6 Synthesis and stepwise dehydrogenation of guanidine 10

An air stream was continuously passed through a magnetically stirred solution of N,N′,N″-tris(benzylamino)guanidinium chloride (3-Cl, 100 mg) in (CD3)2SO while aqueous NaOH (5 m, 0.15 mL) was gradually added from a syringe. The solution instantly developed a yellow color and turned deep orange after 10 min. The progress of the reaction was monitored by NMR spectroscopy, showing the formation of guanidines 10, 11, 12 and 13 (see Tables 1 and 2), which were not isolated. After 90 h, hydrochloric acid (2 m) was added, whereupon the NMR signals of guanidinium salt 14 appeared. In a parallel experiment, the air stream was replaced by argon. The color of the solution remained yellow and only guanidine 10 was observed, which was re-converted into 3-Cl by addition of hydrochloric acid.

Table 2:

1H and 13C NMR data of guanidine derivatives 1013.

CompoundNMR data (δ values, solvent (CD3)2SO)a
3-Clarticle image1H: 3.73 (s, 6H, 4-H), 5.65 (s, 3H, 3-H), 7.30 (m, 15 H, H), 8.79 (s, 3 H, 2-H)

13C: 54.42 (C-4), 127.36, 128.20, 129.09, 137.01 (ipso-CPh), 156.99 (C-1)
10article image1H: 3.74 (s, 6H, 4-H), 4.45 (s, 3H, 3-H), 6.64 (s, 2H, 2-H), 7.20-7.40 (m, 15H, 5-H)

13C: 55.83 (C-4), 156.06 (C-1)
11article image1H: 3.86 (s, 2H, 8-H), 3.99 (s, 2H, 7-H), 4.86 (s, 1H, 4-H), 5.02 (s, 1H, 5-H), 7.31 (s, 1H, 3-H), 7.65 (s, 1H, 2-H), 7.72 (m, 2H, 9-H), 8.20 (s, 1H, 6-H)

13C: 55.69 (C-7), 55.92 (C-8); 137.01, 138.32, 139.92 (3.i-CPh); 146.88 (C-6), 159.46 (C-1)
12article image1H: 4.08 (d, J=4.0 Hz, 2H, 7-H), 4.89 (dd, J=4.0 and 3.2 Hz, 1H, 4-H), 7.77 (m, 2H, HPh), 7.91 (m, 2H, HPh), 8.08 (d, J=3.2 Hz, 1H, 3-H), 8.28 (s, 1H, 5-H), 8.31 (s, 1H, 6-H), 10.46 (s, 1H, 2-H)

13C: 55.30 (C-7), 142.30 (C-6), 148.70 (C-5), 155.60 (C-1)
13See Section 4.4

a1H spectra measured at 400.13 MHz, T=298 K; 13C spectra measured at 100.61 MHz, T=298 K. Spectra of 26 recorded at T=353 K. Due to overlapping signal sets in the product mixtures, signals of phenyl rings are reported incompletely or not at all. Where necessary, signal assignments were taken from 2D correlation spectra.

4.7 2,4-Dibenzyl-3,3-dimethyl-6-(2-((E)-benzylidene)hydrazin-1-yl)-1,2,3,4-tetrahydro-1,2,4,5-tetrazine (15) and 2,7-dibenzyl-6,6-dimethyl-3-phenyl-2H,3H,4H,6H,7H,8H-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (16)

N,N′,N″-Tris(benzylamino)guanidinium chloride (3-Cl) (350 mg, 0.85 mmol) was suspended in ethyl acetate (45 mL), aqueous NaOH (0.33 m, 45 mL) was added and the biphasic liquid mixture was exposed to ultrasonic irradiation for 5 min. A color change from colorless to yellow was observed. The mixture was transferred into a separatory funnel and the organic phase was extracted with more water, isolated, dried (Na2SO4), and set aside with air contact for 1 h. After solvent evaporation, a viscous yellow oil remained, which was dissolved in acetone (2 mL). Upon addition of pentane by the vapor diffusion method, tufts of columnar pale yellow crystals were formed overnight, which were identified as 1:1 cocrystals of 15 and 16 by XRD analysis. Yield: 199 mg (0.48 mmol, 56%); melting range of 40–140°C. – IR (KBr): ν=3500–2000 (continuous absorption with several maxima), 1626 (m), 1585 (m), 1559 (m), 1489 (m), 1449 (m), 1363 (m), 750 (m), 694 (m) cm−1. – Anal. calcd. for C25H28N6×C25H28N6 (C50H56N12, 825.07 g mol−1): C 72.79, H 6.84, N 20.37; found C 72.81, H 6.73, N 20.29.

NMR data for 15: 1H NMR ((CD3)2SO, 400.13 MHz): δ=1.30 (s, 6 H, CH3), 3.82 (s, 2 H, CH2), 3.92 (s, 2 H, CH2), 7.10–7.50 (m, 15 H, HPh), 7.30 (s, 1 H, CH2NNH), 7.67 (s, 1 H, N=CH), 9.88 (s, 1 H, N=C–NH) ppm. – 13C NMR ((CD3)2SO, 100.61 MHz): δ=20.73 (CH3), 55.11 (CH2), 56.27 (CH2), 70.74 (C(CH3)2), 125.62, 126.08, 126.25, 126.37, 126.52, 127.65, 127.81, 127.94, 128.26, 128.44, 128.54, 128.61, 128.68, 128.77, 129.20 (CHPh, 15 and 16), 135.70, 138.19, 139.48, 139.57, 139.67, 141.37 (CPh, both compounds), 136.38 (N=CH), 141.37 (NH–C=N) ppm.

NMR data for 16: 1H NMR ((CD3)2SO, 400.13 MHz): δ=1.22 (s, 3 H, CH3), 1.30 (s, 3 H, CH3), 3.18 and 3.60 (AB spin system, 2 H, 2J=13.2 Hz, CHAHB–NC(CH3)2), 3.44 (d, 1 H, J=11.6 Hz, CHPh), 3.70 and 4.01 (AB spin system, 2 H, 2J=12.8 Hz, CHAHB–NCH), 5.32 (d, 1 H, J=11.6 Hz, NHCH), 7.10–7.50 (m, 15 H, HPh), 7.49 (s, 1 H, NHC=N) ppm. – 13C NMR ((CD3)2SO, 100.61 MHz): δ=20.32 (CH3), 20.73 (CH3), 56.31 (CH2NCH), 58.33 (CH2N–C(CH3)2), 74.99 (CHPh), 83.67 (C(CH3)2), 149.50 (NHC=N) ppm.

4.8 Crystal structure determinations

Experimental details and crystal data are given in the Supporting Information available online (see below). Molecule plots were prepared using Ortep-3 for Windows [30] or Mercury [31].

5 Supporting information

Experimental details, crystal data and numbers pertinent to data collection and structure refinement of (5a5b) SO4·2H2O, 6, 7, 13 and 15·16 are given as supplementary material available online (DOI: 10.1515/znb-2019-0216).

CCDC 1964851 ((5a·5b)SO4·2H2O), 1964852 (6), 1964856 (7), 1964858 (13) and 1964862 (15·16) contain the crystallographic data for this paper in CIF form. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Acknowledgements

We thank B. Müller (Institute of Inorganic Chemistry II, University of Ulm) for the X-ray data collections.

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Footnotes

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/znb-2019-0216).

Footnotes

Article note

For part 5, see ref. [1].

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [1]

    J. Szabo, J. Greiner, G. Maas, Beilstein J. Org. Chem.201713, 579–588.

  • [2]

    C. von Eßen, C. R. Göb, I. M. Oppel, in Guanidines as Reagents and Catalysts IITopics in Heterocyclic Chemistry, Vol. 51 (Ed.: P. Selig), Springer, Cham, 2015, pp. 75–94.

  • [3]

    F. L. Scott, M. Cashman, J. Reilly, J. Am. Chem. Soc.195274, 5802.

  • [4]

    K. N. Zelenin, A. G. Saminskaya, O. B. Kuznetsova, Zh. Obshch. Khim.199666, 141–146.

  • [5]

    I. M. Müller, R. Robson, Angew. Chem. Int. Ed.200039, 4357–4359.

  • [6]

    J. Szabo, G. Maas, Z. Naturforsch.201368b, 207–213.

  • [7]

    I. M. Müller, D. Möller, Eur. J. Inorg. Chem.2005, 257–263.

  • [8]

    W. Plass, A. S. El-Tabl, A. Pohlmann, J. Coord. Chem.200962, 358–372.

  • [9]

    N. Bucher, J. Szabo, I. M. Oppel, G. Maas, Z. Naturforsch.201267b, 631–642.

  • [10]

    J. Szabo, K. Karger, N. Bucher, G. Maas, Beilstein J. Org. Chem.201410, 2255–2262.

  • [11]

    J. Szabo, J. Greiner, G. Maas, Beilstein J. Org. Chem.201713, 579–588.

  • [12]

    V. Jurćík, R. Wilhelm, Tetrahedron200460, 3205–3210.

  • [13]

    G. Godin, B. Levrand, A. Trachsel, J.-M. Lehn, A. Herrmann, Chem. Commun.201046, 3125–3127.

  • [14]

    B. Buchs (née Levrand), G. Godin, A. Trachsel, J.-Y. de Saint Laumer, J.-M. Lehn, A. Herrmann, Eur. J. Org. Chem.2011, 681–695.

  • [15]

    Review: M. Ciaccia, S. Di Stefano, Org. Biomol. Chem.201513, 646–654.

  • [16]

    G. H. Merriman, D. M. Fink, B. S. Freed, B. E. Kurys, S. Pavlek, J. Varriana, E. J. Paulus, Synthesis2000, 138–139.

  • [17]

    M. C. Etter, Acc. Chem. Res.199023, 120–126.

  • [18]

    D. E. Lynch, T. Dougall, G. Smith, K. A. Byriel, C. H. L. Kennard, J. Chem. Crystallogr.199929, 67–73; see also cited references.

  • [19]

    G. L. Starova, O. V. Frank-Kamenetskaya, V. V. Makarshii, V. A. Lopirev, Kristallografiya197823, 849–851.

  • [20]

    W.Skorianetz, E. Sz. Kováts, Helv. Chim. Acta197053, 251–262.

  • [21]

    W. Oppolzer, Tetrahedron Lett.1970, 2199–2204.

  • [22]

    V. V. Khau, M. J. Martinelli, Tetrahedron Lett.199637, 4323–4328.

  • [23]

    M. Zhu, N. Zhang, Synthesis201114, 2223–2236.

  • [24]

    H. Li, J. Liang, C. Huo, Chinese J. Chem.201937, 878–882.

  • [25]

    D. A. Chavez, M. A. Hiskey, J. Heterocycl. Chem.199835, 1329–1332.

  • [26]

    K. Kigasawa, M. Hiiragi, N. Wagatsuma, T. Kohagizawa, H. Inoue, JP Patent 54,163,579, 1979.

  • [27]

    G.-W. Rao, W.-X. Hu, Bioorg. Med. Chem. Lett.200616, 3702–3705; and cited literature.

  • [28]

    W.-X. Hu, G.-W. Rao, Y.-Q. Sun, Bioorg. Med. Chem. Lett.200414, 1177–1181.

  • [29]

    S. Weiss, H. Krommer (SKW Trostberg AG), DE 3341645 (A1), 1985; Chem. Abstr.1986104, 206730.

  • [30]

    L. J. Farrugia, J. Appl. Crystallogr.201245, 849–854.

  • [31]

    Mercury (version 3.10.1), Cambridge Crystallographic Data Centre, Cambridge (UK) 20012018.

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  • View in gallery

    Reaction of the N,N′,N″-triaminoguanidinium ion 1 with acetone. aAcetone as solvent, 4 days, r.t.; see ref. [6].

  • View in gallery

    N,N′,N″-Triaminoguanidinium salts 1 and derivatives thereof.

  • View in gallery

    Solid-state structure of the co-crystal of 5a (lower part of picture) and 5b with one SO42− anion and two H2O molecules in the asymmetric unit (Mercury). Hydrogen bonds are shown as blue-violet dashed bonds. N–H⋯O hydrogen bonds connect both cations with sulfate anions (one of the two SO42− ions shown does not belong to the asymmetric unit), and O–H⋯O hydrogen bonds between sulfate anions and water molecules are also present. For the sake of clarity, not all short intermolecular contacts are shown. Selected bond lengths in 5a (Å): C1–N1 1.322, C1–N3 1.323, C1–N5 1.348, N1–N2 1.426, N3–N4 1.425, N5–N6 1.417, C2–N2 1.480, C2–N4 1.479. Selected bond lengths in 5b (Å): C5–N7 1.322, C5–N9 1.336, C5–N11 1.342, N11–N12 1.390, N7–N8 1.417, C6–N8 1.479, C6–N10 1.477, N10–N9 1.428(3); all estimated standard deviations are at ±0.003 Å.

  • View in gallery

    Reaction of tris(benzylamino)guanidinium salt 3-Cl with aldehydes.

  • View in gallery

    Solid-state structure of 6 (Ortep). The molecule has a crystallographic inversion center. Torsion angle C11–N2–N1i–C2i 135.95°.

  • View in gallery

    Solid-state structure of 7 (Mercury). A centrosymmetric dimer is shown, which is maintained by two N–H⋯N hydrogen bonds [distances (Å): N2⋯N4 3.042(2), N4–H 0.89(2), N2⋯H(N4) 2.19(2); angle N2⋯H–N4 159.3(16)°].

  • View in gallery

    Proposed mechanism of the reaction of 3-Cl with aldehydes.

  • View in gallery

    Formation and stepwise dehydrogenation of N,N′,N″-tris(benzylamino)guanidine 10 in basic medium. a=exposure to air.

  • View in gallery

    Solid-state molecular structure of 13 (Ortep). Bond distances (Å): C1–N1 1.356(3), C1–N2 1.329(3), C1–N3 1.343(3), N1–N4 1.371(2), N2–N5 1.406(3), N3–N6 1.388(3), N4–C2 1.277(3), N5–C3 1.260(3), N6–C4 1.299(3).

  • View in gallery

    Molecules 15 (left) and 16 in the 1:1 cocrystal (Ortep). Bond distances (Å) in 15: C1–N1 1.287(2), C1–N3 1.372(2), C1–N5 1.389(2), N5–N6 1.374(2), N6–C19 1.283(2), N1–N2 1.434(2), N3–N4 1.425(2). Bond distances (Å) in 16: C28–N7 1.394(2), C28–N9 1.366(2), C28–N12 1.285(2), N7–N8 1.452(2), N9–N10 1.430(2), N11–N12 1.451(2). Intermolecular hydrogen bonds between 15/15 and 15/16 [d(N–H)/d(H⋯N)/d(N⋯N)/<(N–H⋯N)]: N3–H⋯N4 (−x, −y+1, −z) 0.86 Å/2.42 Å/3.216 Å/155°; N5–H⋯N11 0.99/2.21/3.202/175; N5–H⋯N12 0.99/2.69/3.544/145; N7–H⋯N12 (−x, −y+1, −z+1) 0.87/2.24/3.106/172; N10–H⋯N1) 0.92/2.18/3.059/159.

  • View in gallery

    Synthesis of tetrazinane derivatives 15 and 16 and a mechanistic proposal.