Catalyst-free synthesis of tetrahydropyrimidines via formal [3+3]-cycloaddition of imines with 1,3,5-hexahydro-1,3,5-triazines

A practical and environmentally benign synthesis of poly-substituted tetrahydropyrimidines from readily available starting materials has been developed. This process features an unprecedented intermolecular formal [3+3]-annulation of imines and 1,3,5-hexahydro-1,3,5-triazines under catalyst-free conditions. Importantly, differing from previous transformations, the 1,3,5-triazines are firstly utilized as formal 1,3-dipoles in cycloaddition reactions.

Tetrahydropyrimidines are important heterocycles which have been widely explored in various biologically active molecules and advanced materials, possessing unique properties such as antiviral activity, anti-inammatory, muscarinic agonist activity, and sensitivity to protein-DNA interactions. 1 However, efficient methods for tetrahydropyrimidine synthesis are rare 2 and some of them suffer from poor practicability with low yields, harsh reaction conditions and lack readily available starting materials. Therefore, to develop simple but efficient methodologies for the direct synthesis of polysubstituted tetrahydropyrimidines is highly demanded.
With the optimal conditions in hand, we started to examine the scope of substrates ( Table 2). The reaction of 1,3,5-triazines with an array of imines was carried out at 60 C in toluene. In the beginning, the variation of R 1 and R 2 groups of imines has been evaluated. For N-4-methoxy-substituted imines, the aryl R 1 and R 2 groups bearing electron-donating and electronwithdrawing groups were tolerated, providing the corresponding products (3a-3f) in moderate to good yields. However, longer reaction was required for the imines bearing electron-decient aryl groups (3c-3e), whereas ortho-methyl substituted substrate gave the desired product 3f in 61% yield. Varying R 2 from aryl to alkyl groups furnished 3g (11 h) and 3h (18 h) in 72% and 58% yields, respectively. The carboxylic ester group of R 2 was also amenable to the reaction, and tetrahydropyrimidine 3i was isolated in 74% yield aer 16 h. The reaction of cyclic imine with 2a afforded 3j in 89% yield within 8 h. The molecular structure of 3j was characterized by X-ray diffraction. 11 Next, the scope of N-substituent of imines was examined. It was observed that N-aryl imines with electron-donating substituents gave the corresponding products in higher yields than the ones with electron-withdrawing groups (3k, 3l vs. 3m-3n). The reaction was also applicable to N-alkyl imine and the desired product 3o was isolated in 72% yield. Finally, the scope of 1,3,5-triazines was evaluated. N-aryl-1,3,5-triazines bearing both electron-donating and electron-withdrawing groups were tolerated and the desired products were obtained in moderate to excellent yields (3p to 3t). It should be noted that N-benzhydryl triazine was also tolerated, providing 3u in 79% yield.  To examine the practicability of this protocol, a gram scale reaction was performed (Scheme 2). Treatment of 5 g of 1a (16.6 mmol, 1 equiv.) and 1,3,5-tribenzhydryl-1,3,5-triazine (10.7 g, 18.2 mmol, 1.1 equiv.) at 60 C in toluene for 24 h gave 6.1 g of 3u (72% yield) as white solid aer recrystallization.
Mechanistic studies were conducted to understand the reaction mechanism (Scheme 3). First, the reaction of 1a with aniline and paraformaldehyde in toluene at 60 C for 12 h delivered 3p, 3a and 4 in 42%, 19% and 9% yields, respectively, indicating the exchange of imine with aniline occurred (Scheme 3a). Next, the reaction of 1a and 2a in the presence of 1 equiv. of aniline provided 78% yield of 3a and 7% yield of 3p, providing evidence for the exchange between aniline and 1,3,5-triazine (Scheme 3b). Moreover, treatment of 1a with D-2a in the presence of paraformaldehyde produces D-3a in 80% yield with 35% and 41% of hydrogen incorporation, indicating the decomposition of 1,3,5-triazines to formaldimines and further decomposed to aniline and formaldehyde (Scheme 3c).
Based on the above results, a possible mechanism for the catalyst-free formal [3+3]-cycloaddition is proposed in Scheme 4. The dissolution of 1,3,5-triazine 2a in solvent would generate formaldimine 2a 0 , which can further decompose to 4-methoxyaniline and formaldehyde due to the existence of small amount of water in the solvent. Imine 1a can isomerize to enamine 1a 0 in the reaction system. The whole process might be triggered by a formal aza-ene type reaction 12,1j between enamine 1a 0 and formaldimine 2a 0 , generating active intermediates baminoimine IA or 1,3-diamine IB. These intermediates then react with in situ formed formaldehyde to generate the condensation product tetrahydropyrimidine 3a and release one molecular of water into the reaction system. The role of water and the existence of formaldehyde can be conrmed by the crossover experiments (Scheme 3).
In summary, we have developed a novel protocol to synthesize poly-substituted tetrahydropyrimidines from readily available starting materials under catalyst-free conditions. The process is simple, practical and environmentally benign, proceeding via a formal [3+3]-cycloaddition between imines and 1,3,5-triazines. Typically, the 1,3,5-triazines have been rstly utilized as formal 1,3-dipoles in the cycloaddition reactions, which is unprecedented. Mechanistic studies show that this reaction is a step-wise process, namely the initial reaction of imines with in situ generated formaldimines, followed by condensation with formaldehyde to give the nal product.

Conflicts of interest
There are no conicts to declare.