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