Background and Originality Content
Multicomponent reactions (MCRs) [1] have been extensively studied and are of enormous importance in synthetic organic and medicinal chemistry, due to its step economy and atom efficient nature. [2] This approach also has the potentiality in maximizing the efficiency of the preparation of the compound library with molecular diversity for the needs of drug screening. Notably, to meet the increasing demand for green chemistry, the development of harmless multicomponent reactions is urgent. Solvent-free systems have featured many advantages in reducing waste and pollution, even serious accidents, which might be a “green” answer in laboratory research or industrial production. [3] Therefore, the development of solvent-free multicomponent reactions has been a vibrant work, thereby opening green and efficient method for the diversity synthesis of valuable molecules. [4]
Pyrimidines and the corresponding dihydro-compounds found in many active molecules with a wide range of biological and pharmacological properties, [5] and therefore, attracting extensively attention from the synthetic community.[6] Meanwhile, to provide high-quality platform molecules for drug discovery, the direct introduction of fluoroalkyl group, especially difluoromethyl or trifluoromethyl, into heterocycles represents huge interest for chemical companies.[7,8] In 2017, Bi and Liang [9]reported a novel photoinduced multicomponent cyclization reaction to forge fluoroalkyl-functionalized pyrimidines from active methylenes, perfluoroalkyl iodides, and guanidines/amidines (Scheme 1a). Later on, Loh and Shen[10] reported the radical-polar crossover-enabled formal [3 + 2 + 1] heteroannulation to construct a variety of fluoroalkyl-pyrimidines from silylenol ether, amidines, and fluoroalkyl halide (Scheme 1b). The same group also realized the Cu-catalyzed cascade cyclization of styrenes, amidines, and fluoroalkyl halides to access diverse fluoroalkylated pyrimidines.[11] Despite these achievements, some disadvantages such as excess additives and harmful solvent limit the applications of these approaches. More importantly, although fluoroalkylated pyrimidines have been achieved, the corresponding fluoroalkylated dihydropyrimidines remain elusive. Thus, the discovery of novel strategies fulfilling modern reaction ideals of green chemistry for the switchable synthesis of both fluoroalkylated pyrimidines and dihydropyrimidines are challenging and urgent.
Herein, we wish to report the successful implementation of a switchable [3 + 2 + 1] annulation strategy for the direct construction of diverse fluoroalkylated dihydropyrimidines/pyrimidines under solvent-free conditions, using easily available enaminones, trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol and amidines hydrochloride as substrates (Scheme 1c). This reaction not only conforms to the concept of green synthesis, but also provides a new avenue to access diverse fluorinated heterocycles.
Scheme 1 Significance and synthetic design for fluoroalkylated dihydropyrimidines and pyrimidines.
Results and Discussion
We initiated our studies with readily available ethyl 3-(N ,N -dimethylamino)acrylate (1a ), trifluoroacetaldehyde hydrate (2a ) and benzamidine hydrochloride (3a ) as model substrates. To our delight, a solvent-free and additive-free multicomponent cyclization reaction was conducted to give the desired product 4a in 82% yield after heating at 130 °C for 1 h (Table 1, entry 1), while lower yields were obtained in DMSO, CH3CN or THF as solvent (Table 1, entries 2−4). Decreasing or increasing the ratio of substrate 2a both had negative impact on the yields of4a (Table 1, entries 5−7). Slightly reduced yields were achieved after altering the reaction temperature (Table 1, entries 8 and 9). When the reaction time was extended to 16 h, 4a was obtained in 58% yield, along with the oxidative dehydrogenation product 6a obtained in 8% yield. Fortunately, the yield of 4-CF3-pyrimidines 6awas increased up to 66% yield with CuCl (20 mol%) as catalyst under air atmosphere. Next, various copper salts were evaluated (Table 1, entries 12−15), but none of them were found to be superior to CuCl. Further decreasing the amount of CuCl to 5 mol% failed to give a higher yield of 6a (Table 1, entry 16). However, O2atmosphere did not improve the yield of 6a (Table 1, entry 17). Meanwhile, 6a was obtained in trace amount under N2 atmosphere (Table 1, entry 18).
Table 1 Optimization of the reaction conditionsa