A new and efficient procedure for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones

A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed.

In the same publication, the authors reported another method that was more selective, which involved the addition of two equivalents of a monoalkyl amine (R-NH 2 ) to menadione (6) to give hexahydropyrimidine-fused 1,4-naphthoquinones 5, 11-13 in low yields.

Results and Discussion
Herein we describe a new method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones (13 and 21-25) in high yields, from the sequential reaction of readily available 1,3,5-triazinanes 14-19 with 2-hydroxy-1,4-naphthoquinone (20, or lawsone) under microwave irradiation (Scheme 2).The 1,3,5-triazinanes have several synthetic and biological applications [40].These substances are easily prepared from commercially available amines and formaldehyde in toluene in yields ranging from 75-90%.Barluenga and coworkers [41] have previously shown that 1,3,5-triazinanes undergo fragmentation at elevated temperatures to form 3 equivalents of alkyl-or aryl-formimines in situ.The latter compounds may serve as electrophilic agents for aminoalkylation reactions.Our research group also investigated the aminoalkylation of 2-amino-1,4naphthoquinone with formaldehyde under microwave irradiation to produce two series of N,O-acetals and N,S-acetals.These compounds were obtained in good yields, and several of them showed promising antibacterial activity [42].
The structures of the synthesized 1,3,5-triazinanes were confirmed by spectroscopic techniques such as NMR, 1 H and 13 C-APT, infrared spectroscopy (FTIR) and high resolution mass spectrometry.The synthesis of compounds 14 [43] and 17 [44] has been previously reported in the literature.The structure of compound 18 was confirmed by X-ray diffraction analysis and Figure 2 shows the ORTEP diagram of this compound.The details of the crystal data and refinements are collected in Supporting Information File 1, Table S1.
The crystal structure of compound 18 contains two molecules per asymmetric unit.Two factors explain the differences between molecules A and B (Figure 2): (1) different intermolecular interactions and (2) small differences in the torsion angles of the p-substituted benzyl groups.The 1,3,5-triazinane rings of 18 (molecules A and B) adopt a chair conformation, with Cremer-Pople puckering parameters q 2 and Φ 2 of 0.023(9) Å and 323.0(20)º, respectively, for molecule A, and q 2 and Φ 2 of 0.016(3) Å and 2.0(25)º, respectively, for molecule B.
Next the reaction between 1,3,5-triazinanes 14-19 and 2-hydroxy-1,4-naphthoquinone (20) was developed to prepare fused hexahydropyrimidine-1,4-naphthoquinones 13 and 21-25 using in situ generated alkyl formimines.Performing the reaction without heating proceeds very slow and after 24 hours extensive degradation products were observed.By elevating the temperature and or changing the solvent some product is formed but the yields were very low.On the other hand, when the reactions were conducted in an equimolar ratio under microwave irradiation (300 Monowave model brand Aanton Paar) in chloroform for 15 minutes at a temperature of 150 °C, the desired products were obtained in good yields (75-80%, Scheme 2).All structures of the benzo-fused tetrahydroquinazolines were characterized by 1 H NMR and 13 C-APT, infrared spectroscopy (FTIR) and high resolution mass spectrometry.Using compound 23 as an example, it can be observed that its 1 H NMR spectrum contains a doublet of doublets (J = 0.98 and confirmed the insertion of two imines to form a hexahydropyrimidine ring which is coupled to a 1,4-naphthoquinone moiety.Figure 3 shows the ORTEP diagram of compound 23 and the details of the crystal data and refinements are given in Supporting Information File 1, Table S2.
In the crystal structure, the six-membered nitrogen-containing ring of 23 adopts a half boat conformation (Cremer-Pople puckering parameters [45]

Conclusion
A new method for the synthesis of new heterocyclic hexahydropyrimidines fused to a 1,4-naphthoquinone system (13 and 21-25) was developed.The products were obtained in one step, under microwave irradiation and with excellent yields.This method is a more efficient alternative for the preparation of benzo-fused tetrahydroquinazolindiones than the method described in the literature.The structures of all starting 1,3,5triazinanes and products were confirmed by spectroscopical methods and X-ray diffraction analysis.

Figure 2 :
Figure 2: ORTEP diagram of compound 18 depicted with ellipsoids drawn at the 50% probability level and the atom-numbering scheme.
q 2 and Φ 2 of 0.374(9) Å and 119.0(1)) in which the N(3) atom is located at 0.641(2) Å out of the plane of the other five atoms C(2), N(1), C(4a), C(10) and C(4).A possible mechanism that could explain the formation of the tetrahydrobenzo[g]quinazolines 13 and 21-25 is shown in Scheme 3. It initially involves the in situ formation of three thermally generated iminium ions or the equivalent methylformimines from the corresponding triazinane which then react with lawsone (20) at its two nucleophilic sites, thus forming products (Scheme 3).

Figure 3 :
Figure 3: ORTEP diagram of compound 23 depicted with ellipsoids drawn at the 50% probability level and the atom-numbering scheme.