Chemoselective defluorinative amination of (trifluoromethyl)alkenes with amidines: synthesis of 6-fluoro-1,4-dihydropyrimidines

Abstract

The chemoselective defluorinative amination of (trifluoromethyl)alkenes with amidines is reported. This transition-metal-free method is operationally simple and gram-scalable, tolerates diverse useful functional groups, and gives a variety of synthetically valuable 6-fluoro-1,4-dihydropyrimidines in high yields under mild conditions.

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Introduction

The nitrogen heterocycle dihydropyrimidine is not only a component of the most important nucleic acids, including cytosine, uracil in RNA, and thymine in DNA units, but also has proven to be a privileged skeleton of bioactive molecules in the field of drug discovery.^1,2 For example, compound I is an angiotensin II (AII) receptor antagonist,^2a compound II is a capsid assembly inhibitor for hepatitis B virus (HBV) treatment,^2b and compound III is a potent apelin (APJ, gene symbol APLNR) receptor agonist for the potential treatment of heart failure (Fig. 1).^2c Therefore, considerable efforts have been devoted to developing new and efficient methods for the synthesis of dihydropyrimidine derivatives, such as the famous Biginelli reaction and its variations.³ Generally, these protocols have led to the construction of nonfluorinated 3,4-dihydropyrimidine derivatives (Scheme 1a). Fluorine decoration of potential medicines could enhance the lipophilicity, catabolic stability, and transport rate of the parent molecules.⁴ The monofluoroalkene group is also recognized as a nonisomerizable and nonhydrolyzable bioisostere of the amide.⁵ Thus, the synthesis and application of novel fluorinated heterocycles have attracted considerable attention.⁶ In particular, fluorouracil, which features the dihydropyrimidine skeleton, is an FDA-approved anticancer agent (Fig. 1).^2d Doxifluridine (5′-DFUR) is an important antitumor agent and a non-toxic prodrug of 5-fluorouracil.⁷ It is primarily used in the treatment of solid tumors such as breast cancer and gastrointestinal malignancies.⁸ Tegafur is a nucleoside analogue chemotherapy drug with excellent clinical efficacy. It not only exerts therapeutic effects on tumor-related disorders but is also indicated for treating gastric, rectal, pancreatic, and liver cancers.⁹ However, the attractive fluorinated dihydropyrimidines have still rarely been synthesized.

Fig. 1 Selected bioactive compounds with dihydropyrimidine skeletons.

Scheme 1 Background.

Amidines are readily available building blocks to construct nitrogen heterocycles.¹⁰ Defluorinative amination¹¹ represents a straightforward and efficient method to synthesize nitrogen compounds with fluorine decoration, although basic conditions are usually necessary to ensure the reaction reactivity. However, owing to the resonance stabilization of amidines under basic conditions, the defluorinative amination of amidines intrinsically suffers from issues of chemoselectivity between the two nucleophilic nitrogen sites (Scheme 1b).¹² In our previous study, we reported a bond energy-enabled amine-distinguishing strategy via defluorinative amination with readily available (trifluoromethyl)alkenes.¹³ Inspired by this, as well as our continuous interest in the synthesis of fluorinated heterocycles via defluorinative amination of (trifluoromethyl)alkenes with indoles and sulfonamides,^13,14 we herein report the chemoselective defluorinative amination of (trifluoromethyl)alkenes with amidines under mild conditions, delivering diverse attractive 6-fluoro-1,4-dihydropyrimidines in high yields (Scheme 1c).

Results and discussion

The initial experiment was carried out with (trifluoromethyl)alkene 1a and N-phenylpivalimidamide 2a in the presence of Li₂CO₃ in DMSO at 35 °C for 18 h (Table 1, entry 1). However, owing to the weak basicity and poor solubility of Li₂CO₃, the defluorinative amination reaction between (trifluoromethyl)alkene 1a and N-phenylpivalimidamide 2a did not occur, and the desired 6-fluoro-1,4-dihydropyrimidine 3aa was not detected. To our delight, the use of the strong base Cs₂CO₃ afforded product 3aa in 19% yield (entry 2). Thus, the influence of diverse inorganic and organic bases was examined (entries 3–11). Organic bases such as DBU, DABCO, and Et₃N could not deliver 3aa (entries 9–11). Therefore, the different interactions between the C–F bonds and alkali–metal ions (Li⁺, Na⁺, and K⁺),¹⁵ as well as the different basicity and solubility of LiOH, NaOH, KOH, t-BuOLi, t-BuONa, and t-BuOK, had a significant impact on the yield of the product 3aa. The strong base t-BuOLi furnished the desired product 3aa in 70% yield (entry 6). Predictably, in the absence of a base, no reaction occurred (entry 12). Furthermore, the impact of different solvents was also investigated (entries 13–19). Strong polar aprotic solvents were beneficial to this reaction, and the solvent DMF produced 3aa in 63% yield. However, less-polar solvents such as MeCN, 1,4-dioxane, THF, toluene, DCE, and the protic solvent EtOH could not give 3aa. Increasing or decreasing the reaction temperature slightly eroded the yield of 3aa (entries 20 and 21). Additionally, performing this reaction under an N₂ atmosphere did not further enhance the yield of 3aa, indicating that this reaction was not sensitive to air and moisture (entry 22). Significantly, the isomer 3aa′ was not detected under any of these conditions.

Table 1 Optimization of reaction conditions^a

Entry	Base	Solvent	Temperature (°C)	Yield of 3aa ^b (%)
a The reaction conditions were: 1a (0.3 mmol, 1.5 equiv.), 2a (0.2 mmol, 1 equiv.), base (0.6 mmol, 3 equiv.) in the solvent (2 mL) for 18 h under air. b Yields were determined via^1H NMR spectroscopy of the crude product with 1,3,5-trimethoxybenzene as an internal standard. c Isolated yield. d Under N2 atmosphere. DCE = 1,2-dichloroethane.
1	Li2CO3	DMSO	35	0
2	Cs2CO3	DMSO	35	19
3	LiOH	DMSO	35	0
4	NaOH	DMSO	35	37
5	KOH	DMSO	35	33
6^c	t-BuOLi	DMSO	35	70
7	t-BuONa	DMSO	35	49
8	t-BuOK	DMSO	35	12
9	DBU	DMSO	35	0
10	DABCO	DMSO	35	0
11	Et3N	DMSO	35	0
12	—	DMSO	35	0
13	t-BuOLi	DMF	35	63
14	t-BuOLi	MeCN	35	0
15	t-BuOLi	1,4-Dioxane	35	0
16	t-BuOLi	THF	35	0
17	t-BuOLi	toluene	35	0
18	t-BuOLi	DCE	35	0
19	t-BuOLi	EtOH	35	0
20	t-BuOLi	DMSO	25	65
21	t-BuOLi	DMSO	50	56
22^d	t-BuOLi	DMSO	35	69

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Under the optimized reaction conditions (Table 1, entry 6), we examined the scope of (trifluoromethyl)alkenes 1 in this chemoselective reaction with N-phenylpivalimidamide 2a as the reaction partner. The obtained results are shown in Scheme 2. This electron-neutral 2-naphthyl-substituted (trifluoromethyl)alkene delivered 3aa in 70% yield. 2-Aryl (trifluoromethyl)alkenes with electron-donating substituents such as methyl, tert-butyl, alkoxy, and amino groups and electron-withdrawing substituents such as fluoro, chloro, bromo, ester, trifluoromethyl, and cyano groups at different positions of the phenyl ring all delivered the desired products 3ba–3ma in 53–68% yields. Significantly, 3ja proved to be crystalline, and its structure was determined by means of X-ray crystallographic analysis.¹⁶ Despite the strong basic conditions, 2-aryl (trifluoromethyl)alkenes bearing an ester group or a cyano group smoothly delivered the desired products 3ka (53% yield) and 3ma (67% yield). Product 3la was obtained in 60% yield, clearly demonstrating the excellent chemoselectivity between the two different CF₃ groups in this defluorinative amination reaction. It also indicates that the alkene moiety plays a crucial role in this reaction. Heteroaromatic quinolinyl and benzo[b]thiophen-3-yl substituted (trifluoromethyl)alkenes smoothly gave 3na (69% yield) and 3oa (50% yield). 2-Alkynyl (trifluoromethyl)alkenes also seemed to be good substrates, providing products 3pa and 3qa in high yields under the standard conditions. Interestingly, in the presence of the in situ-generated fluoride, the TIPS group of 3qa was maintained. Importantly, the high unsaturation of the alkynes in the obtained products of 3pa and 3qa provides a powerful platform for structural diversification.¹⁷ However, 2-bromo-3,3,3-trifluoroprop-1-ene, 2-cyclohexyl (trifluoromethyl)alkene and (2-(trifluoromethyl)allyl)benzene could not afford the corresponding products 3ra–3ta. These three substituents are unable to satisfy the core mechanistic prerequisites of this reaction, which was primarily attributed to steric hindrance impeding nucleophilic attack and electronic effects that attenuate reaction activity.

Scheme 2 Scope of (trifluoromethyl)alkenes. Unless otherwise noted, the reaction conditions were: 1 (0.6 mmol, 1.5 equiv.), 2a (0.4 mmol, 1 equiv.), t-BuOLi (1.2 mmol, 3 equiv.) in DMSO (4 mL) at 35 °C for 18 h. Isolated yields. ^a ORTEP representation of the crystal structure of 3ja with thermal ellipsoids set at 50% probability, H atoms are omitted for clarity.

Furthermore, the scope of amidines was investigated (Scheme 3). As expected, N-arylpivalimidamides with electron-donating substituents such as methyl and iso-propyl groups and electron-withdrawing substituents such as fluoro, chloro, and bromo at different positions of the phenyl ring provided the corresponding products 3ab–3ag in 71–82% yields. However, the reaction between N-cyclohexylpivalimidamide 2h and (trifluoromethyl)alkene 1a did not proceed, even at 80 °C and using the different bases Cs₂CO₃, t-BuONa, and t-BuOK, which might be related to the poor reactivity of N-cyclohexylpivalimidamide 2h. Interestingly, when N-phenylcyclohexanecarboximidamide 2i and N-phenylbutyrimidamide 2j were used as the reactants, their reactions with (trifluoromethyl)alkene 1a proceeded smoothly under the standard reaction conditions. However, the corresponding products 3ai and 3aj decomposed completely during column chromatography on silica gel or aluminum oxide. In addition, N-phenylbenzimidamide 2k provided 3ak in 50% yield.

Scheme 3 Scope of amidines.Unless otherwise noticed, the reaction conditions were: 1a (0.6 mmol, 1.5 equiv.), 2 (0.4 mmol, 1 equiv.), t-BuOLi (1.2 mmol, 3 equiv.) in DMSO (4 mL) at 35 °C for 18 h. Isolated yields.

The reaction was scaled up to 7 mmol (Scheme 4a) and provided 3aa in 60% yield (1.504 g). Defluorinative oxidation of 3aa with SeO₂ afforded compound 4 in 80% yield (Scheme 4b). Finally, editing the dihydropyrimidine skeleton of 3aavia treatment with NH₃ delivered product 5, featuring a 1H-imidazole core building block in 50% yield (Scheme 4c). We proposed a possible pathway for the formation of 5 based on control experiments (see SI for details). Nucleophilic attack of ammonia on the fluorinated pyrimidine derivative 3aa generates intermediate A with a positively charged amino group. Subsequently, a rearrangement occurs, converting the pyrimidine ring into the amidine compound B. Then, upon hydrolysis and elimination of ammonium fluoride, the carboxylic acid derivative C is formed. This carboxylic acid undergoes oxidation in the presence of oxygen and water to yield the five-membered ring D. Finally, further oxidation, accompanied by the release of carbon dioxide and water, affords the product 5 (Scheme 4d).

Scheme 4 Gram-scale experiment and synthetic applications.

Based on the obtained results in previous literature,^13,14,18 two possible pathways were proposed and are shown in Scheme 5. Deprotonation of amidine 2 with an alkali–metal base gives the nitrogen anion E, which also exists in its resonance form as the nitrogen anion E′. In pathway I,^13,14 the ipso-selective defluorinative amination of (trifluoromethyl)alkene 1 with nitrogen anion E′ provides the gem-difluoroalkylated intermediate F. In the presence of an alkali–metal base, deprotonation of F delivers the nitrogen anion G, which is then converted to the product 3via the intramolecular γ-selective defluorinative amination. In pathway II,¹⁸ the nitrogen anion E undergoes γ-selective defluorinative amination with (trifluoromethyl)alkene 1 to afford intermediate H. Deprotonation of H with an alkali–metal base affords nitrogen anion I, which subsequently isomerizes to nitrogen anion I′via resonance. The following intramolecular S_NV reaction of intermediate I′ gives the product 3.

Scheme 5 Proposed mechanism.

Conclusions

In summary, we demonstrated the chemoselective defluorinative amination of (trifluoromethyl)alkenes with amidines, affording various attractive 6-fluoro-1,4-dihydropyrimidines in high yields under mild conditions. This transition-metal-free method is operationally simple and gram-scalable, and tolerates diverse useful functional groups. The utilization of this defluorinative amination reaction in polymerization is currently ongoing in our laboratory.

Experimental

General information

Chemical shifts are reported in ppm using the solvent resonance as the internal standard (CDCl₃δ_H = 7.26 ppm, δ_C = 77.16 ppm). Multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are reported in hertz (Hz). ¹H, ¹³C and ¹⁹F NMR data were recorded using a Bruker Avance III 500 MHz. IR spectra were obtained with an infrared spectrometer from either potassium bromide pellets or liquid films between two potassium bromide pellets. HRMS was carried out using a high-resolution mass spectrometer (Agilent 6210 ACPI/TOF MS). TLC was performed using commercially available 100–400 mesh silica gel plates (GF 254). Visualization was typically performed using UV light. X-ray structural analyses were conducted using a Bruker APEX-II CCD Diffractometer. Commercially available reagents and solvents were purchased and used without further purification. Analytical thin-layer chromatography was performed on 0.20 mm silica gel plates (GF254) using UV light as a visualizing agent. Flash column chromatography was carried out using silica gel (200–300 mesh) with the indicated solvent system. All reactions were conducted in oven-dried Schlenk tubes. All the reaction temperatures reported are oil bath temperatures. For optimization of the reaction conditions, the yield of 3aa was determined via¹H NMR spectroscopy of the crude product with 1,3,5-trimethoxybenzene as the internal standard. Isolated yields are presented for the newly synthesized products in this manuscript. In the substrate scope experiments, (trifluoromethyl)alkene 1r was purchased directly, and (trifluoromethyl)alkenes 1a–1q and 1s–1t were synthesized according to reports in the literature.^19aN-Arylamidine 2k was purchased directly, and N-arylamidines 2a–2j were synthesized according to reports in the literature.^19b

General procedure for defluorinative cyclization of (trifluoromethyl)alkenes with N-arylamidines

In a 25 mL oven-dried Schlenk tube equipped with a magnetic stirring bar, (trifluoromethyl)alkenes 1 (0.6 mmol, 1.5 equiv.), N-arylamidines 2 (0.4 mmol, 1 equiv.), t-BuOLi (96 mg, 1.2 mmol, 3 equiv.), and DMSO (4 mL) were vigorously stirred at 35 °C for 18 h. Stirring was then stopped, water was added (15 mL), and the mixture was extracted with diethyl ether (10 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Further purification by flash column chromatography on silica gel (eluted with petroleum ether/ethyl acetate) provided the product 3.

Procedure for the gram-scale synthesis

In a 50 mL oven-dried round-bottom flask equipped with a magnetic stirring bar, 1a (2.331 g, 10.5 mmol, 1.5 equiv.), 2a (1.232 g, 7 mmol, 1 equiv.), t-BuOLi (1.680 g, 21 mmol, 3 equiv.), and DMSO (15 mL) were vigorously stirred at 35 °C for 18 h. Stirring was stopped, water was added (100 mL), and the mixture was extracted with diethyl ether (50 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Further purification by flash column chromatography on silica gel (eluted with petroleum ether/ethyl acetate) provided the product 3aa (1.504 g, 60% yield).

2-(tert-Butyl)-6-fluoro-5-(naphthalen-2-yl)-1-phenyl-1,4-dihydropyrimidine (3aa)

100.2 mg, 70% yield; yellow solid; mp: 72–73 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.74–7.86 (m, 4H), 7.61–7.68 (m, 1H), 7.33–7.51 (m, 7H), 4.74 (d, J = 10.0 Hz, 2H), 1.15 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.6 (d, J = 2.5 Hz), 148.4 (d, J = 262.5 Hz), 140.4 (d, J = 2.5 Hz), 133.5, 132.0, 131.8 (d, J = 5.0 Hz), 129.7, 129.3, 128.1, 128.0, 127.8, 127.6, 126.1, 125.8, 125.5 (d, J = 7.5 Hz), 125.3 (d, J = 5.0 Hz), 92.6 (d, J = 12.5 Hz), 49.6, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.5. IR (KBr): 2994, 1770, 1702, 1245, 1056, 816, 748.3 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₄H₂₄FN₂⁺, 359.1918; found, 359.1914.

2-(tert-Butyl)-6-fluoro-1-phenyl-5-(p-tolyl)-1,4-dihydropyrimidine (3ba)

81.8 mg, 63% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.44 (m, 5H), 7.25–7.31 (m, 2H), 7.09–7.17 (m, 2H), 4.57 (d, J = 10.0 Hz, 2H), 2.33 (s, 3H), 1.09 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.8 (d, J = 3.8 Hz), 147.7 (d, J = 260.0 Hz), 140.6 (d, J = 2.5 Hz), 136.2, 131.3 (d, J = 5.0 Hz), 129.6, 129.2, 129.1, 128.0, 126.8 (d, J = 5.0 Hz), 92.7 (d, J = 13.8 Hz), 49.6, 39.6, 30.4, 21.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.7. IR (KBr): 2955, 1704, 1285, 1219, 1153, 814, 699 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₁H₂₄FN₂⁺, 323.1918; found, 323.1914.

2-(tert-Butyl)-5-(4-(tert-butyl)phenyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidine (3ca)

99.1 mg, 68% yield; yellow solid; mp: 85–86 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.28–7.44 (m, 9H), 4.60 (d, J = 10.0 Hz, 2H), 1.32 (s, 9H), 1.10 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.9 (d, J = 2.5 Hz), 149.4, 147.9 (d, J = 261.3 Hz), 140.7 (d, J = 2.5 Hz), 131.2 (d, J = 5.0 Hz), 129.5, 129.2, 128.0, 126.6 (d, J = 6.3 Hz), 125.3, 92.7 (d, J = 13.8 Hz), 49.5, 39.6, 34.6, 31.4, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.3. IR (KBr): 2962, 2869, 1706, 1491, 1286, 838, 699 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₄H₃₀FN₂⁺, 365.2388; found, 365.2371.

2-(tert-Butyl)-5-(3,4-dimethylphenyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidine (3da)

88.3 mg, 65% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 8 : 1); eluted with petroleum ether/ethyl acetate = 8 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.44–7.30 (m, 5H), 7.19 (s, 1H), 7.15–7.07 (m, 2H), 4.56 (d, J = 10.0 Hz, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.10 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.8 (d, J = 2.5 Hz), 147.6 (d, J = 261.3 Hz), 140.7 (d, J = 2.5 Hz), 136.5, 134.9, 131.7 (d, J = 5.0 Hz), 129.7, 129.5, 129.2, 128.2 (d, J = 6.3 Hz), 128.0, 124.4 (d, J = 5.0 Hz), 92.9 (d, J = 13.8 Hz), 49.7, 39.6, 30.4, 20.0, 19.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.8. IR (KBr): 2957, 1706, 1491, 1259, 1152, 885, 759 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₂H₂₆FN₂⁺, 337.2075; found, 337.2074.

2-(tert-Butyl)-6-fluoro-5-(4-methoxyphenyl)-1-phenyl-1,4-dihydropyrimidine (3ea)

87.4 mg, 64% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 5 : 1); eluted with petroleum ether/ethyl acetate = 5 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.28–7.43 (m, 7H), 6.83–6.92 (m, 2H), 4.55 (d, J = 10.0 Hz, 2H), 3.79 (s, 3H), 1.09 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.9 (d, J = 2.5 Hz), 158.1, 147.3 (d, J = 258.8 Hz), 140.7 (d, J = 2.5 Hz), 129.5, 129.2, 128.1 (d, J = 5.0 Hz), 128.0, 126.6 (d, J = 5.0 Hz), 113.9, 92.5 (d, J = 13.8 Hz), 55.3, 49.6, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −105.6. IR (KBr): 2957, 2930, 1707, 1249, 1034, 830, 700 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₁H₂₄FN₂O⁺, 339.1867; found, 339.1858.

2-(tert-Butyl)-6-fluoro-5-(3-methoxyphenyl)-1-phenyl-1,4-dihydropyrimidine (3fa)

76.5 mg, 57% yield; yellow oil; R_f = 0.3 (petroleum ether/ethyl acetate = 5 : 1); eluted with petroleum ether/ethyl acetate = 5 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.38–7.27 (m, 5H), 7.16–7.22 (m, 1H), 6.86–6.96 (m, 2H), 6.66–6.76 (m, 1H), 4.52 (d, J = 10.0 Hz, 2H), 3.74 (s, 3H), 1.04 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.7 (d, J = 2.5 Hz), 159.6, 148.2 (d, J = 261.3 Hz), 140.4 (d, J = 2.5 Hz), 135.6 (d, J = 5.0 Hz), 129.6, 129.3, 129.3, 128.1, 119.4 (d, J = 5.0 Hz), 112.6 (d, J = 5.0 Hz), 112.2, 92.57, 92.46(d, J = 13.8 Hz), 55.3, 49.5, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.4. IR (KBr): 2956, 2833, 1704, 1365, 1151, 776, 697 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₁H₂₄FN₂O⁺, 339.1867; found, 339.1866.

4-(2-(tert-Butyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidin-5-yl)-N,N-diphenylaniline (3ga)

100.8 mg, 53% yield; yellow solid; mp: 92–93 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.41 (m, 2H), 7.32–7.36 (m, 3H), 7.26–7.30 (m, 2H), 7.21–7.25 (m, 4H), 7.07–7.10 (m, 4H), 7.03–7.06 (m, 2H), 6.98–7.02 (m, 2H), 4.57 (d, J = 10.0 Hz, 2H), 1.10 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.8 (d, J = 2.5 Hz), 147.7, 147.7(d, J = 260.0 Hz), 146.1, 140.6 (d, J = 2.5 Hz), 129.5, 129.3, 129.2, 128.3 (d, J = 5.0 Hz), 128.0, 127.8 (d, J = 3.8 Hz), 124.3, 123.8, 122.9, 92.46 (d, J = 13.8 Hz), 49.4, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.2. IR (KBr): 2967, 1704, 1511, 1492, 1279, 732, 697 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₃₂H₃₁FN₃⁺, 476.2497; found, 476.2487.

2-(tert-Butyl)-6-fluoro-5-(4-fluorophenyl)-1-phenyl-1,4-dihydropyrimidine (3ha)

78.2 mg, 60% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.51–7.27 (m, 7H), 7.06–6.95 (m, 2H), 4.54 (d, J = 10.0 Hz, 2H), 1.08 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.7 (d, J = 3.8 Hz), 161.3 (dd, J = 243.8, 2.5 Hz), 147.9 (d, J = 261.3 Hz), 140.4 (d, J = 2.5 Hz), 130.3 (dd, J = 5.0, 3.8 Hz), 129.6, 129.3, 128.5 (dd, J = 8.8, 6.3 Hz), 128.2, 115.3 (d, J = 21.3 Hz), 91.8 (d, J = 13.8 Hz), 49.6, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.6, −115.5. IR (KBr): 2967, 1707, 1512, 1260, 1234, 834, 700 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₀H₂₁F₂N₂⁺, 327.1667; found, 327.1674.

2-(tert-Butyl)-5-(3-chlorophenyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidine (3ia)

90.2 mg, 66% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.29 (m, 6H), 7.26–7.09 (m, 3H), 4.53 (t, J = 10.0 Hz, 2H), 1.13–1.03 (m, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.4, 148.6 (d, J = 262.5 Hz), 134.0, 136.1 (d, J = 5.0 Hz), 134.3, 129.7, 129.6, 129.3, 128.3, 127.0 (d, J = 6.3 Hz), 126.4, 124.9 (d, J = 6.3 Hz), 91.3 (d, J = 12.5 Hz), 49.2, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −102.5. IR (KBr): 2958, 2927, 1703, 1257, 1151, 730, 699 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₀H₂₁ClFN₂⁺, 343.1372; found, 343.1374.

5-(4-Bromophenyl)-2-(tert-butyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidine (3ja)

100.4 mg, 65% yield; yellow solid; mp: 89–90 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.46 (m, 7H), 7.20–7.26 (m, 2H), 4.54 (d, J = 5.0 Hz, 2H), 1.08 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.5 (d, J = 3.8 Hz), 148.3 (d, J = 262.5 Hz), 140.0 (d, J = 2.5 Hz), 133.2 (d, J = 6.3 Hz), 131.5, 129.7, 129.3, 128.5 (d, J = 6.3 Hz), 128.3, 120.0 (d, J = 1.3 Hz), 91.4 (d, J = 13.8 Hz), 49.2, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.1. IR (KBr): 2953, 2833, 1701, 1365, 1256, 763, 698 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₀H₂₁BrFN₂⁺, 387.0867; found, 387.0856.

Methyl 4-(2-(tert-butyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidin-5-yl)benzoate (3ka)

77.6 mg, 53% yield; yellow solid; mp: 105–106 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 7 : 1); eluted with petroleum ether/ethyl acetate = 7 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.91–7.99 (m, 2H), 7.35–7.44 (m, 4H), 7.27–7.34 (m, 3H), 4.55 (d, J = 10.0 Hz, 2H), 3.85 (s, 3H), 1.04 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 167.0, 164.1 (d, J = 3.8 Hz), 149.1 (d, J = 263.8 Hz), 139.7, 139.1(d, J = 5.0 Hz), 129.8, 129.6, 129.3, 128.4, 127.6, 126.5 (d, J = 6.3 Hz), 91.4 (d, J = 13.8 Hz), 52.1, 49.0, 39.6, 30.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −101.0. IR (KBr): 2954, 1721, 1699, 1279, 1151, 762, 701 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₂H₂₄FN₂O₂⁺, 367.1816; found, 367.1813.

2-(tert-Butyl)-6-fluoro-1-phenyl-5-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrimidine (3la)

90.2 mg, 60% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 8 : 1); eluted with petroleum ether/ethyl acetate = 8 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.53–7.59 (m, 2H), 7.44–7.50 (m, 2H), 7.44–7.33 (m, 5H), 4.58 (d, J = 10.0 Hz, 2H), 1.08 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.3 (d, J = 3.8 Hz), 149.1 (d, J = 262.5 Hz), 139.7 (d, J = 2.5 Hz), 138.0 (d, J = 5.0 Hz), 129.8, 129.4, 128.5, 128.2, 126.9 (d, J = 6.3 Hz), 125.3 (q, J = 3.8 Hz), 123.3, 91.1 (d, J = 13.8 Hz), 49.1, 39.7, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.5, −101.8. IR (KBr): 2976, 2931, 1700, 1499, 1400, 1102, 690 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₁H₂₁F₄N₂⁺, 377.1635; found, 377.1640.

4-(2-(tert-Butyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidin-5-yl)benzonitrile (3ma)

89.2 mg, 67% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 5 : 1); eluted with petroleum ether/ethyl acetate = 5 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.60–7.51 (m, 2H), 7.47–7.28 (m, 7H), 4.55 (d, J = 5.0 Hz, 2H), 1.06 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 163.9 (d, J = 3.8 Hz), 149.6 (d, J = 265.0 Hz), 139.3 (d, J = 1.3 Hz), 139.2 (d, J = 6.3 Hz), 132.1, 129.9, 129.3, 128.6, 127.1 (d, J = 6.3 Hz), 119.2, 109.2 (d, J = 2.5 Hz), 90.4 (d, J = 12.5 Hz), 48.6, 39.6, 30.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −99.9. IR (KBr): 2954, 1697, 1262, 1151, 837, 722, 701 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₁H₂₁FN₃⁺, 334.1714; found, 334.1725.

7-(2-(tert-Butyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidin-5-yl)quinoline (3na)

99.2 mg, 69% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 5 : 1); eluted with petroleum ether/ethyl acetate = 5 : 1; ¹H NMR (500 MHz, CDCl₃) δ 8.82 (dd, J = 4.3, 1.7 Hz, 1H), 7.99–8.08 (m, 2H), 7.79–7.89 (m, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.29–7.43 (m, 6H), 4.67 (d, J = 5.0 Hz, 2H), 1.09 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.3 (d, J = 3.8 Hz), 150.1, 148.8 (d, J = 262.5 Hz), 146.9, 140.0 (d, J = 2.5 Hz), 135.9, 132.7 (d, J = 6.3 Hz), 129.7, 129.3, 129.2, 129.1, 129.0, 128.3, 124.8 (d, J = 5.0 Hz), 121.4, 91.7 (d, J = 12.5 Hz), 49.4, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −102.7. IR (KBr): 2967, 2928, 1700, 1494, 1264, 837, 700 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₃H₂₃FN₃⁺, 360.1871; found, 360.1857.

5-(Benzo[b]thiophen-2-yl)-2-(tert-butyl)-6-fluoro-1-phenyl-1,4-dihydropyrimidine (3oa)

72.8 mg, 50% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J = 10.0 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.32–7.46 (m, 7H), 7.30 (s, 1H), 4.59 (d, J = 10.0 Hz, 2H), 1.14 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 165.3 (d, J = 3.8 Hz), 148.1 (d, J = 260.0 Hz), 140.5 (d, J = 3.8 Hz), 140.0, 137.7, 130.0 (d, J = 3.8 Hz), 129.4, 129.4, 128.1, 124.4, 124.2, 124.2, 123.3(d, J = 3.8 Hz), 122.9, 88.9 (d, J = 17.5 Hz), 50.9, 39.8, 30.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −99.9. IR (KBr): 2957, 2927, 1713, 1253, 1151, 760, 732 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₂H₂₂FN₂S⁺, 365.1482; found, 365.1481.

2-(tert-Butyl)-6-fluoro-1-phenyl-5-(phenylethynyl)-1,4-dihydropyrimidine (3pa)

83.6 mg, 63% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.33–7.44 (m, 5H), 7.24–7.33 (m, 5H), 4.38 (d, J = 5.0 Hz, 2H), 1.04 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 163.2 (d, J = 3.8 Hz), 153.8 (d, J = 265.0 Hz), 139.5 (d, J = 2.5 Hz), 131.4, 129.8, 129.3, 128.5, 128.4, 128.1, 123.5, 92.7 (d, J = 3.8 Hz), 82.2 (d, J = 3.8 Hz), 77.1, 49.6, 39.8, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −92.8. IR (KBr): 2961, 1702, 1491, 1293, 1149, 755, 691 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₂H₂₂FN₂⁺, 333.1762; found, 333.1769.

2-(tert-Butyl)-6-fluoro-1-phenyl-5-((triisopropylsilyl)ethynyl)-1,4-dihydropyrimidine (3qa)

107.2 mg, 65% yield, yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.37–7.45 (m, 3H), 7.29–7.34 (m, 2H), 4.33 (d, J = 5.0 Hz, 2H), 1.08–1.11 (m, 21H), 1.06 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 163.0, 154.5 (d, J = 265.0 Hz), 139.4, 129.9, 129.3, 128.5, 119.9, 99.4 (d, J = 3.8 Hz), 94.4 (d, J = 5.0 Hz), 49.6, 39.8, 30.4, 18.7, 11.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −92.7. IR (KBr): 2944, 2866, 1701, 1365, 883, 762, 676 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₅H₃₈FN₂Si⁺, 413.2783; found, 413.2770.

2-(tert-Butyl)-6-fluoro-5-(naphthalen-2-yl)-1-(p-tolyl)-1,4-dihydropyrimidine (3ab)

122.0 mg, 82% yield; yellow solid; mp: 88–89 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 8 : 1); eluted with petroleum ether/ethyl acetate = 8 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.56 (m, 4H), 7.38 (d, J = 5.0 Hz, 1H), 7.12–7.21 (m, 2H), 7.02 (d, J = 5.0 Hz, 2H), 6.93 (d, J = 10.0 Hz, 2H), 4.47 (d, J = 10.0 Hz, 2H), 2.10 (s, 3H), 0.88 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.4 (d, J = 3.8 Hz), 148.4 (d, J = 261.3 Hz), 138.1, 137.4 (d, J = 2.5 Hz), 133.4, 131.9, 131.9 (d, J = 5.0 Hz), 129.8, 129.6, 127.9, 127.7, 127.5, 126.1, 125.6, 125.5 (d, J = 6.3 Hz), 125.1 (d, J = 3.8 Hz), 91.9 (d, J = 13.8 Hz), 49.5, 39.5, 30.4, 21.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.9. IR (KBr): 3055, 2967, 1700, 1508, 1227, 815, 748 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₅H₂₆FN₂⁺, 373.2075; found, 373.2068.

2-(tert-Butyl)-6-fluoro-1-(4-isopropylphenyl)-5-(naphthalen-2-yl)-1,4-dihydropyrimidine (3ac)

115.2 mg, 72% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.75–7.86 (m, 4H), 7.64–7.69 (m, 1H), 7.43–7.52 (m, 2H), 7.27–7.36 (m, 4H), 4.74 (d, J = 10.0 Hz, 2H), 2.94–3.02 (m, 1H), 1.31 (d, J = 5.0 Hz, 6H), 1.16 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.8, 149.2, 148.4 (d, J = 261.3 Hz), 137.6, 133.5, 132.0, 131.9 (d, J = 5.0 Hz), 129.8 (d, J = 5.0 Hz), 129.6, 128.0, 127.8, 127.6, 127.2, 126.2, 125.7, 125.5 (d, J = 7.5 Hz), 125.2 (d, J = 5.0 Hz), 92.1 (d, J = 13.8 Hz), 49.4, 39.6, 33.9, 30.4, 24.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.8. IR (KBr): 2961, 2870, 1700, 1507, 1265, 1150, 746 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₇H₃₀FN₂⁺, 401.2388; found, 401.2385.

2-(tert-Butyl)-6-fluoro-1-(4-fluorophenyl)-5-(naphthalen-2-yl)-1,4-dihydropyrimidine (3ad)

109.8 mg, 73% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 10 : 1); eluted with petroleum ether/ethyl acetate = 10 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.65–7.70 (m, 3H), 7.63 (s, 1H), 7.50 (dt, J = 8.7, 1.7 Hz, 1H), 7.28–7.37 (m, 2H), 7.20–7.27 (m, 2H), 6.99 (t, J = 8.5 Hz, 2H), 4.60 (d, J = 5.0 Hz, 2H), 1.01 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.4 (d, J = 3.8 Hz), 162.2 (d, J = 247.5 Hz), 148.0 (d, J = 261.3 Hz), 136.0, 133.4, 132.1, 131.5 (d, J = 8.8 Hz), 128.0, 127.9, 127.6, 126.2, 125.8, 125.4, 125.4 (d, J = 2.5 Hz), 125.3, 116.2 (d, J = 22.5 Hz), 92.6 (d, J = 13.8 Hz), 49.4, 39.6, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.5, −112.8. IR (KBr): 2966, 2928, 1703, 1505, 1217, 838 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₄H₂₃F₂N₂⁺, 377.1824; found, 377.1807.

2-(tert-Butyl)-1-(4-chlorophenyl)-6-fluoro-5-(naphthalen-2-yl)-1,4-dihydropyrimidine (3ae)

127.0 mg, 81% yield; yellow solid; mp: 81–80 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.75–7.81 (m, 3H), 7.73 (s, 1H), 7.60 (dt, J = 8.8, 1.6 Hz, 1H), 7.40–7.47 (m, 2H), 7.35–7.39 (m, 2H), 7.27–7.32 (m, 2H), 4.69 (d, J = 10.0 Hz, 2H), 1.12 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.3 (d, J = 3.8 Hz), 147.9 (d, J = 262.5 Hz), 138.9 (d, J = 3.8 Hz), 133.9, 133.4, 132.1, 131.5 (d, J = 5.0 Hz), 130.8, 129.5, 128.0, 127.9, 127.6, 126.2, 125.9, 125.4 (d, J = 3.8 Hz), 125.4, 93.2 (d, J = 12.5 Hz), 49.5, 39.7, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.0. IR (KBr): 2967, 2870, 1677, 1490, 1092, 816 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₄H₂₃ClFN₂⁺, 393.1528; found, 393.1517.

2-(tert-Butyl)-1-(3-chlorophenyl)-6-fluoro-5-(naphthalen-2-yl)-1,4-dihydropyrimidine (3af)

111.2 mg, 71% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.63–7.70 (m, 3H), 7.63 (s, 1H), 7.45–7.51 (m, 1H), 7.27–7.36 (m, 3H), 7.17–7.23 (m, 2H), 7.12–7.17 (m, 1H), 4.58 (d, J = 10.0 Hz, 2H), 1.02 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.3 (d, J = 3.8 Hz), 147.9 (d, J = 261.3 Hz), 141.7 (d, J = 2.5 Hz), 134.7, 133.4, 132.1, 131.4 (d, J = 5.0 Hz), 130.2, 129.4, 128.3, 128.0, 127.9, 127.6, 127.5, 126.2, 125.9, 125.4, 125.4, 125.4, 93.9 (d, J = 13.8 Hz), 49.5, 39.7, 30.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.3. IR (KBr): 2966, 2928, 1703, 1588, 1270, 746, 475 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₄H₂₃ClFN₂⁺, 393.1528; found, 393.1528.

1-(4-Bromophenyl)-2-(tert-butyl)-6-fluoro-5-(naphthalen-2-yl)-1,4-dihydropyrimidine (3ag)

139.6 mg, 80% yield; yellow solid; mp: 99–100 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.63–7.69 (m, 3H), 7.60 (s, 1H), 7.44–7.49 (m, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.27–7.35 (m, 2H), 7.11 (dd, J = 8.6, 1.4 Hz, 2H), 4.56 (d, J = 5.0 Hz, 2H), 0.99 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 164.3 (d, J = 3.8 Hz), 147.9 (d, J = 262.5 Hz), 139.5 (d, J = 2.5 Hz), 133.4, 132.5, 132.1, 131.5 (d, J = 5.0 Hz), 131.1, 128.0, 127.9, 127.6, 126.3, 125.9, 125.5 (d, J = 1.3 Hz), 125.4, 122.0, 93.3 (d, J = 13.8 Hz), 49.5, 39.7, 30.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −103.9. IR (KBr): 3055, 2967, 1702, 1485, 1268, 855, 747 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₄H₂₃BrFN₂⁺, 437.1023; found, 437.1010.

6-Fluoro-5-(naphthalen-2-yl)-1,2-diphenyl-1,4-dihydropyrimidine (3ak)

75.6 mg, 50% yield; yellow oil; R_f = 0.4 (petroleum ether/ethyl acetate = 4 : 1); eluted with petroleum ether/ethyl acetate = 4 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.70–7.78 (m, 4H), 7.59–7.64 (m, 1H), 7.46–7.50 (m, 2H), 7.35–7.43 (m, 2H), 7.12–7.19 (m, 7H), 7.06–7.11 (m, 1H), 4.92 (d, J = 10.0 Hz, 2H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 155.4 (d, J = 1.3 Hz), 150.5, 147.3 (d, J = 260.0 Hz), 138.9, 134.5 (d, J = 1.3 Hz), 133.4, 132.1, 131.5 (d, J = 5.0 Hz), 129.8, 129.1 (d, J = 5.0 Hz), 128.6 (d, J = 1.3 Hz), 128.1, 128.0, 127.9, 127.6, 127.4, 126.3, 125.9, 125.5 (d, J = 7.5 Hz), 125.4 (d, J = 5.0 Hz), 89.9 (d, J = 11.3 Hz), 50.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −106.1. IR (KBr): 3057, 1702, 1492, 1271, 912, 749, 696 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd for C₂₆H₂₀FN₂⁺, 379.1605; found, 379.1592.

2-(tert-Butyl)-5-(naphthalen-2-yl)-1-phenylpyrimidin-4(1H)-one (4)

To a 25 mL oven-dried Schlenk tube equipped with a magnetic stirring bar, 3aa (179.0 mg, 0.5 mmol, 1 equiv.), SeO₂ (138.8 mg, 1.25 mmol, 2.5 equiv.) were added. The tube was evacuated and filled with N₂, and 1,4-dioxane (3 mL) was added. The mixture was sealed and vigorously stirred at 100 °C for 12 h. After completion of the reaction (monitored by TLC analysis), the reaction mixture was quenched with H₂O (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were then dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Further purification by flash column chromatography on silica gel (eluted with petroleum ether/ethyl acetate) provided the product 4 in 80% isolated yield.

283.2 mg, 80% yield; white solid; mp: 237–238 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 9 : 1); eluted with petroleum ether/ethyl acetate = 9 : 1; ¹H NMR (500 MHz, CDCl₃) δ 8.37 (s, 1H), 8.33 (s, 1H), 7.78–7.89 (m, 4H), 7.44–7.58 (m, 5H), 7.32 (d, J = 10.0 Hz, 2H), 1.22 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 166.4, 163.4, 149.9, 138.2, 133.4, 133.1, 130.8, 130.1, 129.5, 129.1, 128.5, 128.0, 127.8, 127.6, 126.3, 126.2, 125.9, 124.2, 40.7, 30.8. IR (KBr): 2969, 1679, 1510, 1351, 822, 764, 704 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd For C₂₄H₂₃N₂O⁺, 355.1805; found, 355.1794.

2-(tert-Butyl)-5-(naphthalen-2-yl)-1-phenyl-1H-imidazole (5)

To a 25 mL oven-dried Schlenk tube equipped with a magnetic stirring bar, 3aa (107.4 mg, 0.3 mmol, 1 equiv.) and NH₃ (0.4 M) solution in 1,4-dioxane (3 mL) was added. The mixture was vigorously stirred at 100 °C for 48 h under air. After completion of the reaction (monitored by TLC analysis), the reaction mixture was quenched with H₂O (15 mL), extracted with EtOAc (10 mL × 3). The combined organic layers then were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Further purification by flash column chromatography on silica gel (eluted with petroleum ether/ethyl acetate) provided the product 5 in 50% isolated yield.

163.1 mg, 50% yield; white solid; mp: 222–223 °C; R_f = 0.4 (petroleum ether/ethyl acetate = 5 : 1); eluted with petroleum ether/ethyl acetate = 5 : 1; ¹H NMR (500 MHz, CDCl₃) δ 7.67–7.73 (m, 1H), 7.57–7.62 (m, 2H), 7.46 (s, 1H), 7.41–7.31 (m, 7H), 7.25 (s, 1H), 7.18 (dd, J = 8.6, 1.8 Hz, 1H), 1.30 (s, 9H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 156.6, 138.7, 135.7, 133.1, 132.2, 130.1, 129.1, 128.9, 128.0, 127.8, 127.6, 127.5, 127.1, 126.4, 126.2, 126.1, 125.9, 34.8, 30.6. IR (KBr): 2963, 2926, 1489, 1378, 1277, 814, 751 cm⁻¹; HRMS (ESI, m/z): [M + H]⁺ Calcd For C₂₃H₂₃N₂⁺, 327.1856; found, 327.1843.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information (SI): experimental section and characterization of all products, are presented in the manuscript and SI. Copies of the ¹H, ¹³C, and ¹⁹F spectra for all products. See DOI: https://doi.org/10.1039/d5ob01554e.

CCDC 2475106 (3ja) contains the supplementary crystallographic data for this paper.¹⁶

Acknowledgements

We thank the National Natural Science Foundation of China (22271097), the Guangdong Basic and Applied Basic Research Foundation (2022A1515240017), the Sinopec Seed Program, the Open Fund of State Key Laboratory of Green Pesticide, South China Agricultural University (gplscau202409), and the Open Fund of Guangdong Provincial Key Laboratory of Technique and Equipment for Macromolecular Advanced Manufacturing, South China University of Technology (2024kfkt01) for financial support of our programs.

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