Novel Reaction of N,N'-Bisarylmethanediamines with Formaldehyde. Synthesis of Some New

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.

In the present work, the reactions of some N,N'-bisarylmethylenediamines 5a-c as well as arylamines with aqueous formaldehyde were found to produce the corresponding 1,3,5-triaryl-1,3,5hexahydrotriazines 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(2pyrimidinyl)-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].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 1 H-and 13 C-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 1 H-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 AB 2 pattern corresponding to the aromatic moieties.It also gave a correct elemental analysis for C 15 H 15 N 9 . .The proton decoupled 13 C-NMR spectrum showed four 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 1 H-and 13 C-NMR spectra of compounds 6b and 6c were similar to those of 6a.

HCOOH
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.The 1 H-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 D 2 O 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 AB 2 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.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.With the exception of aqueous glyoxal, which produced 2,4,6,8-tetraphenyl-2,4,6,8-tetraazabicyclo[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.

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-1,3,5hexahydrotriazines.

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 1 H-and 13 C-NMR spectra were recorded in DMSO-d 6 on a Bruker DRX-500 AVANCE spectrometer (operating at 500 MHz for 1 H and 125.77MHz for 13 C, respectively), except for the 1 H-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 F 254 .

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