Novel Reaction of N,N'-Bisarylmethanediamines with Formaldehyde. Synthesis of Some New 1,3,5-Triaryl-1,3,5-hexahydrotriazines

Abstract

The acid-catalyzed cyclocondensation of N,N'-bisaryl (aryl = 2-pyrimidinyl, 2-pyrazinyl and 4-nitrophenyl) methanediamines 5a-c with aqueous formaldehyde in refluxing acetonitrile leads to the formation of the corresponding 1,3,5-triaryl-1,3,5-hexa-hydrotriazines 6a-c. The stoichiometric reactions of 2-aminopyrimidine and 2-amino-pyrazine with aqueous formaldehyde in acetonitrile under reflux conditions also afforded 6a and 6b, respectively. Treatment of 2-aminopyrimidine with aqueous formaldehyde in a 3:2 ratio yielded N,N',N"-tris(2-pyrimidinyl)dimethylenetriamine (7a) as a sole product, which upon subsequent reaction with formaldehyde also afforded 6a. The reaction of N,N'-biphenylmethanediamine with formaldehyde was also investigated.

Introduction

The reactions of amines and aldehydes (especially formaldehyde) have been the subject of several publications [1,2,3,4,5,6,7,8]. However, there are still unanswered questions about the reaction mechanism(s) and the nature of the products. The best specific example of this type is the reaction between ammonia and formaldehyde leading to the formation of hexamine (1). Based on chemical and spectroscopic evidence, Nielsen and Richmond concluded that 1,3,5-hexahydrotriazine (R = H, 2) is a reaction intermediate [9,10]. They also suggested the intermediacy of methylenediamine (3) and dimethylene-triamine (4) in the reaction course (Figure 1). We are not aware, however, of any direct evidence that has been reported for the existence of such intermediates.

Figure 1. Structures of hexamine (1), 1,3,5-hexahydrotriazine (2), methylenediamine (3) and dimethylenetriamine (4).

Figure 1. Structures of hexamine (1), 1,3,5-hexahydrotriazine (2), methylenediamine (3) and dimethylenetriamine (4).

On the other hand, numerous accounts of the synthesis of 1,3,5-trisubstituted 1,3,5-hexahydro-triazines from amines and formaldehyde can be found in the literature. 1,3,5-Hexahydrotriazines are important building blocks in high-explosive compounds [11].

In the present work, the reactions of some N,N'-bisarylmethylenediamines 5a-c as well as aryl-amines with aqueous formaldehyde were found to produce the corresponding 1,3,5-triaryl-1,3,5-hexahydrotriazines 6a-c under reflux conditions. In the case of 2-aminopyrimidine, by changing the ratio of amine to formaldehyde, we could isolate the corresponding dimethylenetriamine 7a, which upon subsequent reaction with another molecule of formaldehyde, led to the formation of 1,3,5-tris(2-pyrimidinyl)-1,3,5-hexahydrotriazine (6a). The latter procedure may be considered as an alternative synthetic route to 6a.

Results and Discussion

N,N'-Bisarylmethylenediamines are easily prepared through the reaction of primary arylamines with formaldehyde at room temperature [12,13,14,15]. In the presence of formic acid, the N,N'-bisarylmethylene-diamines 5a-c underwent a smooth reaction with aqueous formaldehyde in refluxing acetonitrile to produce 1,3,5-triaryl-1,3,5-hexahydrotriazines 6a-c in good yields (Scheme 1). A synthesis of 6c has already been described in the literature [16].

Scheme 1. Formic acid catalized reaction of N,N'-bisarylmethylenediamines 5a-c with aqueous formaldehyde.

Scheme 1. Formic acid catalized reaction of N,N'-bisarylmethylenediamines 5a-c with aqueous formaldehyde.

Triazines 6a-c are stable materials and can be stored at room temperature for extended periods. Their structures were determined from their elemental analysis, MS, IR and high-field ¹H- and ¹³C-NMR spectra. For example, the mass spectrum of 6a displayed a weak but distinct peak at 321 m/z for the molecular ion. The IR spectrum lacks both amine and carbonyl absorptions. Its ¹H-NMR spectrum exhibited a sharp singlet at δ = 5.77 ppm, arising from the methylene protons. The remaining protons of the molecule showed a well-resolved AB₂ pattern corresponding to the aromatic moieties. It also gave a correct elemental analysis for C₁₅H₁₅N₉. The proton decoupled ¹³C‑NMR spectrum showedfour distinct resonances, also in agreement with the proposed structure. Finally, the structure of 6a was further confirmed by synthesis via an alternate route (vide infra). The ¹H- and ¹³C-NMR spectra of compounds 6b and 6c were similar to those of 6a.

Scheme 2. Reactions of 2-aminopyrimidine and 2-aminopyrazine with aqueous formaldehyde.

Scheme 2. Reactions of 2-aminopyrimidine and 2-aminopyrazine with aqueous formaldehyde.

The stoichiometric reaction of 2-aminopyrimidine and 2-aminopyrazine with aqueous formaldehyde in refluxing acetonitrile also afforded compounds 6a and 6b respectively (Scheme 2). On the other hand, N,N',N"-tris(2-pyrimidinyl)dimethylenetriamine (7a) was the sole product formed when 2‑aminopyrimidine was reacted with formaldehyde in a 3:2 molar ratio. Its subsequent reaction with additional formaldehyde gave 6a in 82% yield (Scheme 3). This pathway can be viewed as an alternative synthesis of 6a (vide supra).

Scheme 3. Synthesis of N,N',N"-tris(2-pyrimidinyl)dimethylenetriamine (7a) and 6a.

Scheme 3. Synthesis of N,N',N"-tris(2-pyrimidinyl)dimethylenetriamine (7a) and 6a.

The ¹H-NMR spectrum of compound 7a showed a doublet localized at δ = 5.31 ppm for the methylene groups. The NH protons appeared as a wide triplet at δ = 7.31 ppm. Upon addition of D₂O to the NMR samples, the NH signal disappeared and the methylene proton signal collapsed to a singlet. The pyrimidinyl moieties appeared as two well-resolved AB₂ spin systems at 6.65, 8.32 and 6.77, 8.44 ppm. With compound 7a in hand, we were able to follow the reaction of 5a with formaldehyde (Scheme 2) by periodically withdrawing reaction samples and comparing the R_f values of the products with that of 7a using thin-layer chromatography (TLC). The implication of 7a as an intermediate in this reaction was confirmed by its appearance and disappearance on the TLC plate. Based on the above-mentioned observations, our proposed mechanism for the formation of 6a from aqueous formaldehyde and 2-aminopyrimidine is depicted in Scheme 4.

Scheme 4. Proposed mechanism for the formation of 6a.

Scheme 4. Proposed mechanism for the formation of 6a.

The acid-catalyzed reaction of N,N'-bisphenylmethanediamine (5d) with aqueous formaldehyde was also carried out in refluxing acetonitrile as well as at room temperature. Surprisingly, in both cases, 1,3,5,7-tetraphenyltetrazocine (8, m.p. 298-300 °C decomp.) was quickly formed in high yield (Scheme 5). Randaccio and co-workers had already reported the synthesis of 8 through the reaction of aniline and paraformaldehyde in toluene under reflux conditions [2].

Scheme 5. Reaction of N,N'-bisphenylmethanediamine (5d) with aqueous formaldehyde.

Scheme 5. Reaction of N,N'-bisphenylmethanediamine (5d) with aqueous formaldehyde.

With the exception of aqueous glyoxal, which produced 2,4,6,8-tetraphenyl-2,4,6,8-tetraaza-bicyclo[3.3.0]octane (9) upon reaction with 5d, other aldehydes such as benzaldehyde, acetaldehyde, chloral and propionaldehyde all failed to produce any recognizable products (Scheme 6). Synthesis of compound 9 via the reaction of aniline with glyoxal and formaldehyde has previously been reported [17]. It seems likely that 5d may be implicated as an intermediate in the reaction.

Scheme 6. Reaction of N,N'-biphenylmethanediamine (5d) with aqueous glyoxal.

Scheme 6. Reaction of N,N'-biphenylmethanediamine (5d) with aqueous glyoxal.

Conclusions

We have found that the reactions of aqueous formaldehyde with N,N'-bisarylmethylenediamines having electron withdrawing groups on the aromatic rings leads to the formation of 1,3,5-triaryl-1,3,5-hexahydrotriazines.

Experimental

General

All commercially available chemicals and reagents were used without further purification. Melting points were determined with an Electrothermal model 9100 apparatus and are uncorrected. IR spectra were recorded on a Shimadzu 4300 spectrophotometer. The ¹H- and ¹³C-NMR spectra were recorded in DMSO-d₆ on a Bruker DRX-500 AVANCE spectrometer (operating at 500 MHz for ¹H and 125.77 MHz for ¹³C, respectively), except for the ¹H-NMR spectra of compounds 8 and 9, which were recorded on an 80 MHz Bruker AC-80 instrument. Chemical shifts (δ) are reported in ppm and are referenced to the NMR solvent peak. Mass spectra of the products were obtained with a HP (Agilent Technologies) 5937 Mass Selective Detector. Elemental analyses were carried out with a Thermo Finnigan (FLASH 1112 SERIES EA) CHNS-O analyzer. Progress of the reactions was monitored by TLC using precoated aluminium sheets silica gel Merck 60 F₂₅₄.

General procedures for the synthesis of 1,3,5-triaryl-1,3,5-hexahydrotriazines 6a-c

Procedure A

A stirring solution of N,N'-bisarylmethylenediamine (5a-c, 1 mmol), 37% aqueous formaldehyde (0.08 g, 1 mmol) and 98% aqueous formic acid (0.01 g, 0.22 mmol) in acetonitrile (20 mL) was refluxed for 20 hours. The resulting solution was then cooled to 0-5 °C and the solid formed was filtered off, washed with cold acetonitrile and dried.

1,3,5-Tris(2-pyrimidinyl)-1,3,5-hexahydrotriazine (6a): White crystals (70%); m.p. 228-230 °C (from acetonitrile); IR (KBr): 3058, 2902, 1587, 1483, 1352, 1263, 960 cm^-1; ¹H-NMR δ: 5.81 (s, 6H, CH₂), 6.79 (t, 3H, J = 4.7 Hz, pyrimidine H-5), 8.47 (d, 6H, J = 4.7 Hz, pyrimidine H-4, H-6); ¹³C-NMR δ: 57.17, 111.79, 158.30, 161.30 ppm; MS (EI) m/z: 321 (M⁺); Anal. Calcd. for C₁₅H₁₅N₉: C, 56.07; H, 4.67; N, 39.25; Found: C, 55.96; H, 4.69; N, 39.40.

1,3,5-Tris(2-pyrazinyl)-1,3,5-hexahydrotriazine (6b): White crystals (79%); m.p. 196-198 °C (from acetonitrile); IR (KBr): 3085, 2912, 1579, 1523, 1317, 1257, 1130, 997 cm^-1; ¹H-NMR δ: 5.72 (s, 6H, CH₂), 7.88 (d, 3H, J = 2.5 Hz, pyrazine H-5), 8.06 (dd, 3H, J = 2.5, 1.1 Hz, pyrazine H-6), 8.62 (d, 3H, J = 1.1 Hz, pyrazine H-3); ¹³C-NMR δ: 59.58, 133.81, 135.06, 142.05, 153.95 ppm; MS (EI) m/z: 321 (M⁺); Anal. Calcd. for C₁₅H₁₅N₉: C, 56.07; H, 4.67; N, 39.25; Found: C, 55.90; H, 4.70; N, 39.01.

1,3,5-Tris(4-nitrophenyl)-1,3,5-hexahydrotriazine (6c): Yellow crystals (62%); m.p. 285-287 °C (from 1:1 DMSO-EtOH, lit. [16] 286-287 °C); IR (KBr): 3076, 2906, 1589, 1490, 1390, 1311, 1230 cm^-1; ¹H-NMR δ: 5.35 (s, 6H, CH₂), 7.23 and 8.10 (AA'BB', 12H, ArH); ¹³C-NMR δ: 63.64, 115.39, 126.41, 139.89, 153.23 ppm; MS (EI) m/z: 450 (M⁺); Anal. Calcd. for C₂₁H₁₈N₆O₆: C, 56.00; H, 4.00; N, 18.66; Found: C, 55.86; H, 3.95; N, 18.83.

Procedure B

A stirring solution of 2-aminopyrimidine (or 2-aminopyrazine) (0.19 g, 2 mmol), 37% aqueous formaldehyde (0.16 g, 2 mmol) and 98% aqueous formic acid (0.02 g, 0.22 mmol) in acetonitrile (10 mL) was refluxed for 20 hours. The reaction mixture was then cooled to 0-5 °C and the solid formed was filtered off, washed with cold acetonitrile and dried. Recrystallization from acetonitrile gave pure crystals of 6a (or 6b) in 83% (87%) yield, which had identical melting points and IR and NMR spectra with the products obtained using Procedure A

N,N',N"-Tris(2-pyrimidinyl)dimethylenetriamine (7a)

A stirring solution of 2-aminopyrimidine (0.3 g, 3.15 mmol), 37% aqueous formaldehyde (0.16 g, 2 mmol) and 98% aqueous formic acid (0.02 g, 0.44 mmol) in acetonitrile (10 mL) was refluxed for 15 hours. The reaction mixture was then cooled to 0-5 °C and the solid formed was filtered off, washed with cold acetonitrile and dried. Recrystallization from 1:1 DMSO-H₂O gave white pure crystals of 7a (75%); m.p. 218-220 °C; IR (KBr): 3238 (N-H), 3103, 2979, 1596, 1541, 1460, 1377, 1164 cm^-1; ¹H-NMR δ: 5.31 (d, 4H, J = 6.1 Hz, CH₂), 6.65 (t, 2H, J = 4.7 Hz, pyrimidine H-5), 6.77 (t, 1H, J = 4.7 Hz, pyrimidine H-5'), 7.35 (t, 2H, J = 6.1 Hz, NH), 8.32 (d, 4H, J = 4.7 Hz, pyrimidine H-4, H-6), 8.44 (d, 2H, J = 4.7 Hz, pyrimidine H-4', H-6'); ¹H-NMR (DMSO-d₆ + D₂O) δ: 5.29 (s, 4H, CH₂), 6.65 (t, 2H, J = 4.8 Hz, pyrimidine H-5), 6.76 (t, 1H, J = 4.4 Hz, pyrimidine H-5'), 8.30 (d, 4H, J = 4.8 Hz, pyrimidine H-4, H-6), 8.43 (d, 2H, J = 4.4 Hz, pyrimidine H-4', H-6'); ¹³C-NMR δ: 55.36, 111.97, 112.22, 158.66, 158.79, 162.04, 62.88 ppm; MS (EI) m/z: 309 (M⁺, not seen), 201, 108 (base peak), 96; Anal. Calcd. for C₁₄H₁₅N₉: C, 54.36; H, 4.85; N, 40.77; Found: C, 54.37; H, 4.91; N, 40.91.

Reaction of 7a with aqueous formaldehyde

A stirring solution of 7a (0.31 g, 1 mmol) 37% aqueous formaldehyde (0.08 g, 1 mmol) and 98% aqueous formic acid (0.01 g, 0.22 mmol) in a mixture of acetonitrile (20 mL) and DMF (20 mL) was refluxed for 20 hours. Water (50 mL) was added to the resulting solution and the white solid formed was filtered off and dried. Recrystallization from acetonitrile gave white pure crystals (82%), identical with 6a based on melting point and NMR data.

1,3,5,7-Tetraphenyltetrazocine (8)

A solution of N,N'-bisphenylmethanediamine (5d, 0.2 g, 1 mmol), 37% aqueous formaldehyde (0.08 g, 1 mmol) and 98% aqueous formic acid (0.01 g, 0.22 mmol) in acetonitrile (2 mL) was stirred at room temperature for 2 hours. The white solid formed was then filtered off, washed with cold acetonitrile and dried. Recrystallization from DMSO gave white crystals of 8 (85%), m.p. 298-300 °C (lit. [2] 303 °C); IR (KBr): 3026, 2916, 1596, 1502, 1371, 1261, 1164 cm^-1; ¹H-NMR δ: 4.88 (s, 8H, CH₂), 6.97-7.17 (m, 20H, ArH); MS (EI) m/z: 420 (M⁺); Anal. Calcd. for C₂₈H₂₈N₄: C, 80.00; H, 6.66; N, 13.33; Found: C, 79.82; H, 6.69; N, 13.52.

2,4,6,8-Tetraphenyl-2,4,6,8-tetraazabicyclo[3.3.0]octane (9)

A solution of N,N'-bisphenylmethanediamine (5d, 0.4 g, 2 mmol), glyoxal (40% aqueous solution, 0.14 g, 1 mmol) and formic acid (98% aqueous solution, 0.01 g, 0.22 mmol) in acetonitrile (4 mL) was stirred at room temperature for 5 hours. The white solid formed was then filtered, washed with cold acetonitrile and dried. Recrystallization from acetonitrile gave white crystals of 9 (78%); m.p. 209-210 °C (lit. [17] 210-211 °C); IR (KBr): 3030, 2980, 1595, 1492, 1325 cm^-1; ¹H-NMR δ: 4.63 and 4.82 (ABq, 4H, J = 7.4 Hz, CH₂), 6.39 (s, 2H, CH), 6.75-7.27 (m, 20H, ArH); Anal. Calcd. for C₂₈H₂₆N₄: C, 80.38; H, 6.22; N, 13.39; Found: C, 80.17; H, 6.14; N, 13.55.