a Reaction conditions: 1a (0.2 mmol),2a (0.6 mmol, 75% in water), 3a (0.2 mmol), T °C, solvent (2.0 mL). b Isolated yield.c 1a :2a :3a = 1:1.5:1.d 1a :2a :3a = 1:2:1.e 1a :2a :3a = 1:4:1.
Scheme 2 Substrate scope for fluoroalkylated dihydropyrimidinesa
a 0.20 mmol scale under standard reaction conditions. b isolated yield of product4 or 5 . c gram-scale reaction.
With the optimal reaction conditions in hand, we evaluated the generality of the solvent-free MCRs. As shown in Scheme 2, a variety of conjugated enamines successfully reacted with trifluoroacetaldehyde hydrate and benzamidine hydrochloride. As for enamine esters, including alkyl and benzyl derivatives, were smoothly converted to the desired products (4ah ) in moderate to good yields (68−88%). A gram-scale reaction was conducted to deliver 1.2 g of product4a in 80% yield. Complex molecules, such as enamine esters derived from (+)-menthol and (+)-fenchol also worked well to give the corresponding products in 89% and 72% yields, respectively. Alkyl enaminones with different chain lengths or cycloalkyl and phenyl enaminone were tolerated, but leading to the desired products (4kp ) in 41−60% yields, probably due to the interference of electrophilic carbonyl groups. Interestingly, the reaction was also applicable with alkenyl bridged enaminones, affording the respective product 4q in 51% yield. Moreover, phenylsulfonyl enamine was also found to be compatible with the solvent-free MCR, and the corresponding product 4r was obtained in 75% yield. Next, we examined the generality of aryl amidines hydrochloride. Generally, the ortho -, meta -, orpara -substituted aryl amidines hydrochloride bearing electron-donating groups were found to be compatibility under the optimal reaction conditions, delivering the desired products (5ae ) in 64−79% yields. In addition, different kinds of halo-substituted aryl amidines hydrochloride exhibited good reactivity under standard conditions, and the corresponding products (5fj ) were obtained in satisfactory yields (65−78%). Substrates with strong electron-withdrawing groups at thepara- position of phenyl rings (4-CF3, 4-NO2) were also investigated, affording 5k and 5l in 75% and 83% yields, respectively. Notably, the presence of sensitive group (OH) in aryl amidine hydrochloride did not affect this multicomponent cyclization reaction, affording 5m in 73% yield. In addition, the reaction was also applicable to heteroaryl amidines hydrochloride under standard conditions to afford the desired products in good yields (5n , 82%; 5o , 67%). We also investigated the compatibility of 1-ethoxy-2,2-difluoroethanol, which reacted well with 1a and3a , affording 4-CF2H-1,4-dihydropyrimidines5p in 80% yield.
Scheme 3 Substrate scope for fluoroalkylated pyrimidinesa
a 0.20 mmol scale under standard reaction conditions; b isolated yield of product6 .
Next, the substrate scope for constructing 4-CF3pyrimidines was investigated (Scheme 3). Esteryl enamines with diverse substituent groups reacted smoothly with trifluoroacetaldehyde hydrate and benzamidine hydrochloride, delivering the desired products (6af ) in 49−71% yields. Alkyl or aryl enamine ketones were also tolerated to afford the desired products in slightly lower yields (6g , 38%; 6h , 40%). Moreover, the reactions proceeded smoothly with a variety of aryl amidines hydrochloride under the optimal conditions, affording the corresponding products (6iu ) in moderate yields (40−62%). Finally, 4-CF2H-pyrimidines 6v could be obtained in 71% yield using 1-ethoxy-2,2-difluoroethanol as substrate.
After investigating the substrate scopes and the synthetic application of the solvent-free multicomponent cyclization, control experiments were carried out to investigate the reaction mechanism (Scheme 4a). In order to detect the possible intermediates, the reaction was lowered to 60 °C and reacted for 1 h. Fortunately, the possible intermediates Iand II were confirmed by high-resolution mass spectrometry (HRMS), along with the target product 4a obtained in 8% yield (Scheme 4a-1). However, other possible intermediate III orIV was not found (ESI for detail). This result implied that β-CF3-vinylimine ion might be a key intermediate for this multicomponent cyclization. Moreover, 4-CF3-1,4-dihydropyrimidine could be converted into 4-CF3-pyrimidine in the presence of CuCl under air atmosphere (Scheme 4a-2).
On the basis of the experimental results and literature reports,[13,14] a postulated mechanism is illustrated, as shown in Scheme 5. This multicomponent cyclization starts from the addition of ethyl 3-(N ,N -dimethylamino)acrylate 1a to trifluoroacetaldehyde 2a’ to generate intermediate A , which subsequently undergoes a sequential protonation and dehydration to afford β-CF3-vinylimine ion intermediate B . Once formed, intermolecular [3 + 3] cyclization reaction with intermediate B and benzamidine 3a will occur, leading to the formation of intermediate C . Subsequently, a deamination process of intermediate C provides the product 4a , which could be oxidized to afford 6a under copper-catalyzed aerobic condition. [15]
Scheme 4 Control experiments and proposed mechanism.
Conclusions
In summary, a switchable multicomponent cyclization of enaminones, trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol and amidines hydrochloride for accessing fluoroalkylated dihydropyrimidines and pyrimidines have been developed for the first time. The present multicomponent reaction tolerates a wide range of functional groups and can be performed without solvent. Notably, this strategy not only conforms to the concept of green synthesis, but also provides new opportunities for the sustainable formation of diverse fluorinated heterocyclics, thereby is expected to have widespread applications in pharmaceutical discovery. Further investigations on solvent-free multicomponent cyclization are ongoing in our laboratory.
Experimental
A 15 mL sealed tube with a magnetic stirrer bar was charged with enamine (1 , 1.0 equiv, 0.20 mmol), trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol (2 , 3.0 equiv, 0.60 mmol), amidines (3 , 1.0 equiv, 0.20 mmol). The reaction vessel was stirred at 130 oC in heating mantle for 1 h. After completion of the reaction, the resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether/ethyl acetate = 1:1 ∼ 7:1, V/V) to afford the corresponding product 4 or 5 .
A 15 mL sealed tube with a magnetic stirrer bar was charged with enamine (1 , 1.0 equiv, 0.20 mmol), trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol (2 , 3.0 equiv, 0.60 mmol), amidine (3 , 1.0 equiv, 0.20 mmol), CuCl (0.2 equiv, 0.04 mmol). The reaction vessel was stirred at 130 oC in heating mantle for 16 h. After completion of the reaction, the resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether/ethyl acetate = 2:1 ∼ 100:1, V/V) to afford the corresponding product 6 .
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We gratefully acknowledge the National Natural Science Foundation of China (22071171) and the Natural Science Foundation of Zhejiang Province (LZ22B020003) for financial support of this work.
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