Palladium-catalyzed Hiyama cross-couplings of pyrimidin-2-yl tosylates with organosilanes

Abstract

An efficient palladium-catalyzed Hiyama reaction between various pyrimidin-2-yl tosylates with organosilanes has been developed. The use of CuCl with TBAF as additive is essential for promotion of the construction of the carbon–carbon bond. This procedure shows wide functional group tolerance for electrophilic pyrimidin-2-yl tosylates and has been extended to aromatic amino-substituted pyrimidin-2-yl tosylates, affording the desired C2-aryl and alkenyl pyrimidine derivatives in good to excellent yields.

Keywords

Hiyama reaction pyrimidin-2-yl tosylates organosilanes TBAF arylation

This method proved to be tolerant of various electrophilic pyrimidin-2-yl tosylates as well as nucleophilic trimethoxy(phenyl) silane and vinyltrimethoxysilane.

Introduction

Transition-metal-catalyzed Hiyama coupling of organosilanes with halides has been developed as a routine tool for construction of new C–C bonds including the synthesis of the non-symmetrical biaryls,^1,2 which are important materials for the preparation of polymers, agrochemicals, pharmaceutical intermediates, bioactive molecules, and electronic materials.^3–6 Compared to other organometallic reagents,^7–10 organosilicon reagents have emerged as more competitive nucleophilic partners for cross-coupling reactions due to their high chemical stability, low toxicity, and good compatibility.^11–13 Among the electrophiles employed in Hiyama coupling reactions,^14–18 halides exhibit relatively high reactivity, but they suffer from some drawbacks including harsh conditions for their preparation, with the formation of by-products and environmental pollution.¹⁹ Thus, there is still demand for new electrophilic partners instead of halides for Hiyama reactions.

Enol- and phenol-based tosylates have garnered a great deal of interest in recent years because of their easy preparation from phenols, the good cleavage ability of C–O bonds and the consequent reduction of halide waste.^20–22 Indeed tosylates have been effectively employed as new electrophilc partners for classical cross-coupling reactions.^23–25 Nevertheless, only a few examples of Hiyama reactions of tosylates with silanes have been reported due to the weak polarization of the carbon–silicon bond in organosilicon reagents.^26,27 In 2008, Wu and Zhang reported the Pd(OAc)₂ catalyzed Hiyama coupling of aryl tosylates with silanes for the first time; vinyl tosylates also reacted well under the same conditions.²⁸ Subsequently, in 2010, Sarkar and co-workers efficiently achieved the Hiyama reaction of benzyl tosylates and aryltrialkoxysilane in PEG-600 with nanoparticles as the catalyst.²⁹ In 2013, Hiyama and co-workers described Ni(PPh₃)₂Cl₂ catalyzed Hiyama reactions of aryl tosylates with aryl (trialkyl)silanes (Scheme 1).³⁰ Despite the great successes of aryl and benzylic tosylates in these reactions, the Hiyama coupling of heterocyclic tosylates, especially pyrimidin-2-yl tosylates is scarcely reported in the literature and remains a challenging task.

Scheme 1.

Hiyama reaction of tosylates with organosilanes.

Results and discussion

Pyrimidin-2-yl tosylates were prepared according to the literature.³¹ A set of trial experiments were carried out using pyrimidin-2-yl tosylate 1a and trimethoxy(phenyl)silane as substrates to probe the feasibility of their Hiyama cross-coupling reaction. In the early experiments, several transition metal derivatives such as Fe(acac)₃, CuCl₂, Cu(OAc)₂, NiCl₂, Ni(PPh₃)₂Cl₂, and Ni(acac)₂ were screened but, to our disappointment, no cross-coupling product 3a was detected (Table 1, entries 1–6). Pd(OAc)₂ also exhibited low catalytic activity for this reaction (Table 1, entry 7). Previous studies indicated that Cu(І)-salts may be beneficial for the transmetallation of activated silicanes;^32,33 inspired by this, a small amount of CuCl was added to the reaction system and, gratifyingly, the coupling reaction between pyrimidin-2-yl tosylate and trimethoxy(phenyl)silane proceeded smoothly to give the desired product 3a with a 65% yield in the presence of Pd(OAc)₂ (Table 1, entry 8). A higher yield of 80% was achieved in the presence of PdCl₂ (Table 1, entry 9), but the use of CuI instead of CuCl resulted in a significant decrease in the yield of 3a (Table 1, entry 10). The effect of several ligands on the reaction was also studied subsequently and, compared with dppb, PPh₃, dppe, or dppp, PCy₃ provided the target product 3a in the best yield (Table 1, entries 9 and 11–14). Due to the lower activity of the C–Si bond, the Hiyama coupling of organosilyl reagents usually needs to be activated by a base such as F⁻ or OH⁻.^34,35 As expected, TBAF was necessary to achieve the cross-coupling in 80% yield (Table 1, entry 9), but other fluoride salts, CsF or KF, did not provide the desired product (Table 1, entries 15–61), Cs₂CO₃, NaOH, and K₃PO₄ also failed to promote the cross-coupling reaction (Table 1, entries 17–19). Among the solvents screened, dioxane gave the best results (Table 1, entry 9); other solvents such as THF, toluene and DMF led to a decreasing yield (Table 1, entries 20–22).

Table 1.

Optimization of the Hiyama reaction of pyrimidin-2-yl tosylate 1a and phenyltrimethoxysilane^a.


Entry	Catalyst	Additive	Ligand	Activator	Solvent	Yield^b (%)
1	Fe(acac)₃	–	PCy₃	TBAF	Dioxane	0
2	CuCl₂	–	PCy₃	TBAF	Dioxane	0
3	Cu(OAc)₂	–	PCy₃	TBAF	Dioxane	0
4	NiCl₂	–	PCy₃	TBAF	Dioxane	0
5	Ni(PPh₃)₂Cl₂	–	PCy₃	TBAF	Dioxane	0
6	Ni(acac)₂	–	PCy₃	TBAF	Dioxane	0
7	Pd(OAc)₂	–	PCy₃	TBAF	Dioxane	Trace
8	Pd(OAc)₂	CuCl	PCy₃	TBAF	Dioxane	65
9	PdCl₂	CuCl	PCy₃	TBAF	Dioxane	80
10	PdCl₂	CuI	PCy₃	TBAF	Dioxane	32
11	PdCl₂	CuCl	dppb	TBAF	Dioxane	76
12	PdCl₂	CuCl	PPh₃	TBAF	Dioxane	50
13	PdCl₂	CuCl	dppe	TBAF	Dioxane	63
14	PdCl₂	CuCl	dppp	TBAF	Dioxane	68
15	PdCl₂	CuCl	PCy₃	CsF	Dioxane	0
16	PdCl₂	CuCl	PCy₃	KF	Dioxane	0
17	PdCl₂	CuCl	PCy₃	Cs₂CO₃	Dioxane	0
18	PdCl₂	CuCl	PCy₃	NaOH	Dioxane	0
19	PdCl₂	CuCl	PCy₃	K₃PO₄	Dioxane	0
20	PdCl₂	CuCl	PCy₃	TBAF	THF	Trace
21	PdCl₂	CuCl	PCy₃	TBAF	Toluene	75
22	PdCl₂	CuCl	PCy₃	TBAF	DMF	68
23	–	CuCl	PCy₃	TBAF	Dioxane	0
24	PdCl₂	–	PCy₃	TBAF	Dioxane	Trace

Reaction conditions: pyrimidin-2-yl tosylate 1a (0.2 mmol, 0.082 g), phenyltrimethoxysilane (2.0 equiv., 0.4 mmol, 0.047 g), catalyst (5 mol%, 0.01 mmol), additive (20 mol%, 0.04 mmol), ligand (6 mol%, 0.012 mmol), activator (2.0 equiv., 0.4 mmol), solvent (2 mL), 110 °C, under nitrogen.

Isolated yield after column chromatography.

Subsequently, the necessity of PdCl₂ and CuCl to promote the reaction was also tested, the result showed that no product was detected in the absence of PdCl₂ (Table 1, entry 23) and the reaction conversion was also very low without CuCl (Table 1, entry 24), both PdCl₂ and CuCl were indispensable for the Hiyama reaction of pyrimidin-2-yl tosylates with trimethoxy(phenyl)silane.

Under the optimized conditions, the scope of this reaction was investigated using a range of pyrimidin-2-yl tosylates as the electrophile, and the results are summarized in Table 2. For most cases, the pyrimidin-2-yl tosylates 1 reacted well with trimethoxy(phenyl)silane 2a to generate the desired products 3 in moderate to high yields. Pyrimidin-2-yl tosylates bearing electron-donating R¹ groups such as p-Me and p-OMe gave the products 3b in an 83% yield and 3c in an 87% yield. Substrates bearing electron-withdrawing groups R¹ such as p-F, p-Cl, o-Cl, p-Br, and p-NO₂ also underwent the transformation smoothly to provide 3d–h in 81%, 76%, 72%, 69%, and 81% yields, respectively. In addition, when the substituent group, R² and R³, on the pyrimidine ring was –Et, –Me, or i-Pr, the reaction still proceeded smoothly to give 3i–o in excellent yields. This indicated that electronic effects and the steric hindrance of the substituents had little impact on the reactivity of the pyrimidin-2-yl tosylate.

Table 2.

The Hiyama reaction of pyrimidin-2-yl tosylates with phenyl and vinyl trimethoxysilanes.


Entry	R¹	R²	R³	R⁴	Product	Yield (%)
1	H	Et	Me	Ph	3a	80
2	4-CH₃	Et	Me	Ph	3b	83
3	4-OCH₃	Et	Me	Ph	3c	87
4	4-F	Et	Me	Ph	3d	81
5	4-Cl	Et	Me	Ph	3e	76
6	2-Cl	Et	Me	Ph	3f	72
7	4-Br	Et	Me	Ph	3g	69
8	3-NO₂	Et	Me	Ph	3h	81
9	H	Me	Me	Ph	3i	89
10	4-CH₃	Me	Me	Ph	3j	83
11	4-OCH₃	Me	Me	Ph	3k	85
12	4-F	Me	Me	Ph	3l	78
13	4-Cl	Me	Me	Ph	3m	61
14	H	i-Pr	Me	Ph	3n	88
15	H	Et	i-Pr	Ph	3o	80
16	H	Me	Me	Vinyl	3p	64
17	4-OCH₃	Me	Me	Vinyl	3q	58
18	4-OCH₃	Et	Me	Vinyl	3r	61

The Hiyama reaction was not restricted to the use of trimethoxy(phenyl)silane as nucleophile, and allowed for the arylation of other substituted organosilanes. Notably, the desired products 3p–r were generated in moderate yields when vinyltrimethoxysilane was used as the nucleophilic partner. However, both 4-(chloromethyl)phenyltrimethoxysilane and phenyltrichlorosilane failed to couple with pyrimidin-2-yl tosylate 1a. No desired products were detected at all, which confirmed that trimethoxy(phenyl)silane was more effective than other organosilanes in Hiyama reactions.

To expand further the scope of this novel methodology, aromatic amino-substituted pyrimidin-2-yl tosylates were also tested as electrophilic partners. As illustrated in Table 3, the reaction of the aminopyrimidin-2-yl tosylate 4a with trimethoxy(phenyl)silane proceeded smoothly to give the product 5a in an 84% yield, the p-Me substituted pyrimidin-2-yl tosylates 4b and p-Cl substituted substrate 4c also reacted well with trimethoxy(phenyl)silane, giving the desired products 5b in 86% yield and 5c in 87% yield, respectively. These results suggested that amino-substituted pyrimidin-2-yl tosylates exhibit high reactivity similar to that of pyrimidin-2-yl tosylates in Hiyama reactions.

Table 3.

The Hiyama reaction of aromatic amino pyrimidin-2-yl and pyridin-2-yl tosylates with phenyltrimethoxysilane.


Entry	R	Product	Yield (%)
1	H	5a	84
2	4-Me	5b	86
3	4-Cl	5c	87

Conclusion

In summary, we have developed an efficient protocol for the C2-arylation of pyrimidine derivatives via Pd-catalyzed Hiyama cross-coupling reactions of heteroaromatic tosylates with organosilanes in dioxane at 110 °C. The catalyst system including PdCl₂ and PCy₃ exhibits good tolerance for various substituted pyrimidin-2-yl tosylates bearing both electron-donating groups or electron-withdrawing ones. Meanwhile, the nucleophile partner is not restricted to the use of trimethoxy(phenyl)silane, vinyltrimethoxysilane can also give the desired products in moderate yields. In addition, CuCl and TBAF·3H₂O are crucial for activating the C–Si bond in organosilanes and promoting the Hiyama reaction.

Experimental

Infrared (IR) spectra were recorded on a Nicolet Avatar 36 Fourier transform spectrophotometer in KBr disk. ¹H NMR and ¹³C NMR data analyses were performed on a Varian Mercury plus-400 or plus-600 instrument using tetramethylsilane (TMS) as the internal standard, CDCl₃ as solvent. The ¹H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet), coupling constant (J-values) in Hz, and integration. The chemical shifts for ¹H NMR and ¹³C NMR spectra were recorded in units (ppm). High-resolution mass spectra (HRMS) (electrospray ionization (ESI)) were obtained with a Bruker Daltonics APEX II 47e and an Orbitrap Elite mass spectrometer. Column chromatography was generally performed on silica gel (200–300 mesh) and analytical thin-layer chromatography (TLC) was conducted on silica gel GF254 plates according to standard techniques. Melting points were measured with an XT-4 apparatus. Solvents were dried by standard procedures. Pyrimidin-2-yl tosylates as starting materials were prepared by previously reported procedures of our group,³¹ and other chemical reagents were purchased and used without further purification.

General procedure for synthesis 3a–r and 5a–c

The pyrimidin-2-yl tosylate (0.2 mmol), PdCl₂ (5 mol%, 0.01 mmol), PCy₃ (6 mol%, 0.012 mmol), CuCl (20 mol%, 0.04 mmol), and TBAF·3H₂O (2.0 equiv., 0.4 mmol) were respectively added to the sealed Schlenk tube. The organosilane (2.0 equiv., 0.4 mmol) and toluene (2 mL) were injected into the sealed tube by syringe under a nitrogen atmosphere and the mixture was stirred at 110 °C for 36 h. After completion of the reaction as monitored by thin-layer chromatography (silica gel), the mixture was cooled to ambient temperature, diluted with saturated aqueous NH₄Cl (5 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried with anhydrous MgSO₄ and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:50) to afford products 3a–r and 5a–c.

Ethyl 4-methyl-2,6-diphenylpyrimidine-5-carboxylate (3a):

White solid³⁶; 80% yield; m.p. 66–86 °C (66–67 C); IR (KBr) v (cm⁻¹): 3059, 2978, 2925, 1724, 1535, 1495, 1430, 1259, 1174, 1078; ¹H NMR (600 MHz, CDCl₃): δ 8.56-8.55 (m, 2H), 7.76-7.75 (m, 2H), 7.50-7.47 (m, 6H), 4.21 (q, J= 7.2 Hz, 2H), 2.70 (s, 3H), 1.08 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.5, 165.5, 163.7, 163.6, 138.3, 137.2, 131.1, 130.0, 128.7, 128.6, 128.5, 128.5, 123.4, 61.8, 22.9, 13.7; HRMS (ESI+) m/z: calcd for C₂₀H₁₉N₂O₂ [M + H]⁺: 319.1441; found: 319.1447.

Ethyl 4-methyl-2-phenyl-6-(p-tolyl)pyrimidine-5-carboxylate (3b):

White solid³⁶; 83% yield; m.p. 67–69 °C (66–67 °C); IR (KBr) v (cm⁻¹): 2920, 2848, 1724, 1658, 1537, 1511, 1452, 1375, 1259, 1174, 1076; ¹H NMR (600 MHz, CDCl₃): δ 8.56-8.54 (m, 2H), 7.68 (d, J= 8.2 Hz, 2H), 7.49-7.47 (m, 3H), 7.27 (d, J= 7.2 Hz, 2H), 4.24 (q, J= 7.2 Hz, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 1.13 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.7, 165.2, 163.7, 163.4, 140.3, 137.3, 135.4, 131.0, 129.3, 128.7, 128.5, 128.5, 123.2, 61.8, 22.9, 21.5, 13.8; HRMS (ESI+) m/z: calcd for C₂₁H₂₁N₂O₂ [M + H]⁺: 333.1598; found: 333.1594.

Ethyl 4-(4-methoxyphenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate (3c):

White solid³⁷; 87% yield; m.p. 62–36 °C (64–65 °C); IR (KBr) v (cm⁻¹): 3062, 2924, 2839, 1724, 1537, 1464, 1365, 1259, 1174, 1076; ¹H NMR (400 MHz, CDCl₃): δ 8.46-8.44 (m, 2H), 7.67 (d, J= 8.8 Hz, 2H), 7.38-7.37 (m, 3H), 6.88 (d, J= 8.8 Hz, 2H), 4.15 (q, J= 7.2 Hz, 2H), 3.72 (s, 3H), 2.56 (s, 3H), 1.05 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.7, 165.0, 163.4, 162.5, 161.2, 137.1, 130.8, 130.3, 130.0, 128.4, 128.4, 122.7, 113.8, 61.7, 55.2, 22.7, 13.7; HRMS (ESI+) m/z: calcd for C₂₁H₂₁N₂O₃ [M + H]⁺: 349.1547; found: 349.1542.

Ethyl 4-(4-fluorophenyl)-6-methyl-2-phenyl pyrimidine-5-carboxylate (3d):

White solid³⁶; 81% yield; m.p. 84–86 °C (85–86 °C); IR (KBr) v (cm⁻¹): 3060, 3055, 2922, 1724, 1600, 1537, 1506, 1427, 1363, 1259, 1159, 1076; ¹H NMR (600 MHz, CDCl₃): δ 8.55-8.53 (m, 2H), 7.78-7.76 (m, 2H), 7.51-7.49 (m, 3H), 7.17 (t, J= 8.4 Hz, 2H), 4.24 (q, J= 7.2 Hz, 2H), 2.69 (s, 3H), 1.14 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.4, 165.5, 164.0 (d, J= 248.9 Hz, 1C), 163.7, 163.1, 162.3, 137.0, 134.3 (2C), 131.1, 130.6 (d, J= 8.7 Hz, 1C), 128.6 (d, J= 7.2 Hz, 1C), 123.2, 115.6 (d, J= 21.8 Hz, 1C), 61.9, 22.9, 13.8; ¹⁹F NMR (564 MHz, CDCl₃): δ −110.6; HRMS (ESI+) m/z: calcd for C₂₀H₁₈FN₂O₂ [M + H]⁺: 337.1347; found: 337.1352.

Ethyl 4-(4-chlorophenyl)-6-methyl-2-phenyl pyrimidine-5-carboxylate (3e):

White solid³⁶; 76% yield; m.p. 83–85 °C (83–84 °C); IR (KBr) v (cm⁻¹): 3051, 3014, 2928, 1724, 1536, 1363, 1255, 1174, 1078; ¹H NMR (400 MHz, CDCl₃): δ 8.48-8.45 (m, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.43-7.37 (m, 5H), 4.16 (q, J= 7.2 Hz, 2H), 2.62 (s, 3H), 1.07 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.2, 165.6, 163.7, 162.3, 136.8, 136.6, 136.4, 131.2, 129.9, 128.7, 128.6, 128.5, 123.2, 61.9, 22.8, 13.7; HRMS (ESI+) m/z: calcd for C₂₀H₁₈ClN₂O₂ [M + H]⁺: 353.1051; found: 353.1047.

Ethyl 4-(2-chlorophenyl)-6-methyl-2-phenyl pyrimidine-5-carboxylate (3f):

White solid³⁸; 72% yield; m.p. 101–310 °C (101–102 °C); IR (KBr) v (cm⁻¹): 3053, 2979, 2922, 1724, 1595, 1543, 1432, 1360, 1252, 1178, 1082; ¹H NMR (600 MHz, CDCl₃): δ 8.52-8.51 (m, 2H), 7.51-7.47 (m, 4H), 7.42-7.36 (m, 3H), 4.10 (q, J= 7.2 Hz, 2H), 2.79 (s, 3H), 0.96 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 166.7, 166.6, 164.0, 163.8, 138.0, 137.0, 132.3, 131.3, 130.2, 130.2, 129.6, 128.9, 128.6, 126.7, 123.9, 61.5, 23.7, 13.5; HRMS (ESI+) m/z: calcd for C₂₀H₁₈ClN₂O₂ [M + H]⁺: 353.1051; found: 353.1049.

Ethyl 4-(4-bromophenyl)-6-methyl-2-phenyl pyrimidine-5-carboxylate (3g):

White solid³⁶; 69% yield; m.p. 88–90 °C (87–89 °C); IR (KBr) v (cm⁻¹): 3059, 2984, 2896, 1724, 1587, 1539, 1370, 1259, 1174, 1084; ¹H NMR (400 MHz, CDCl₃): δ 8.51-8.49 (m, 2H), 7.78 (d, J= 8.4 Hz, 2H), 7.44-7.38 (m, 5H), 4.19 (q, J= 7.2 Hz, 2H), 2.63 (s, 3H), 1.06 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.5, 165.4, 163.7, 163.1, 137.1, 137.0, 131.0, 128.9, 128.8, 128.6, 128.5, 127.8, 127.2, 127.2, 123.2, 61.8, 22.9, 13.7; HRMS (ESI+) m/z: calcd for C₂₀H₁₈BrN₂O₂ [M + H]⁺: 397.0546; found: 397.0541.

Ethyl 4-methyl-6-(3-nitrophenyl)-2-phenyl pyrimidine-5-carboxylate (3h):

White solid³⁸; 81% yield; m.p. 120–112 °C (123–125 °C); IR (KBr) v (cm⁻¹): 3052, 2983, 2922, 1718, 1581, 1535, 1352, 1261, 1178, 1074; ¹H NMR (600 MHz, CDCl₃): δ 8.66 (s, 1H), 8.55 (s, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.53 (s, 3H), 4.30 (q, J= 7.2 Hz, 2H), 2.73 (s, 3H), 1.19 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 167.8, 166.2, 164.1, 161.0, 148.3, 139.8, 136.6, 134.5, 131.5, 129.6, 128.7, 128.7, 124.7, 123.7, 123.4, 62.2, 23.1, 13.8; HRMS (ESI+) m/z: calcd for C₂₀H₁₈N₃O₄ [M + H]⁺: 364.1292; found: 364.1296.

Methyl 4-methyl-2,6-diphenylpyrimidine-5-carboxylate (3i):

White solid³⁸; 89% yield; m.p. 87–89 °C (87–89 °C); IR (KBr) v (cm⁻¹): 3059, 2949, 1726, 1603, 1535, 1495, 1257, 1174, 1079; ¹H NMR (600 MHz, CDCl₃): δ 8.56 (s, 2H), 7.76 (s, 2H), 7.50-7.48 (m, 6H), 3.74 (s, 3H), 2.69 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.1, 165.5, 163.8, 163.4, 138.1, 137.1, 131.1, 130.1, 128.7, 128.6, 128.6, 128.4, 123.0, 52.6, 23.0; HRMS (ESI+) m/z: calcd for C₁₉H₁₇N₂O₂ [M + H]⁺: 305.1285; found: 305.1280.

Methyl 4-methyl-2-phenyl-6-(p-tolyl) pyrimidine-5-carboxylate (3j):

White solid³⁸; 83% yield; m.p. 63–56 °C (63–65 °C); IR (KBr) v (cm⁻¹): 3060, 3030, 2947, 2850, 1728, 1612, 1537, 1512, 1390, 1263, 1172, 1078; ¹H NMR (600 MHz, CDCl₃): δ 8.56-8.54 (m, 2H), 7.69 (t, J= 7.8 Hz, 2H), 7.51-7.49 (m, 3H), 7.29 (d, J= 8.4 Hz, 2H), 3.76 (s, 3H), 2.67 (s, 3H), 2.43 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.3, 165.4, 163.7, 163.3, 140.5, 137.2, 135.2, 131.1, 129.4, 128.7, 128.5, 128.4, 122.8, 52.6, 23.0, 21.5; HRMS (ESI+) m/z: calcd for C₂₀H₁₉N₂O₂ [M + H]⁺: 319.1441; found: 319.1447.

Methyl 4-(4-methoxyphenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate (3k):

White solid; 85% yield; m.p. 89–91 °C; IR (KBr) v (cm⁻¹): 3057, 2997, 2945, 2830, 1714, 1606, 1539, 1508, 1253, 1174, 1076; ¹H NMR (600 MHz, CDCl₃): δ 8.56-8.54 (m, 2H), 7.77 (d, J= 9.0 Hz, 2H), 7.50-7.59 (m, 3H), 7.00 (d, J= 8.4 Hz, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.66 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.4, 165.2, 163.6, 162.6, 161.3, 137.3, 131.0, 130.4, 130.0, 128.6, 128.5, 122.4, 114.0, 55.4, 52.6, 22.9; HRMS (ESI+) m/z: calcd for C₂₀H₁₉N₂O₃ [M + H]⁺: 335.1390; found: 335.1395.

Methyl 4-(4-fluorophenyl)-6-methyl-2-phenyl pyrimidine-5-carboxylate (3l):

Yellow oil³⁸; 78% yield; IR (KBr) v (cm⁻¹): 3060, 2924, 1726, 1604, 1539, 1508, 1390, 1263, 1157, 1076; ¹H NMR (600 MHz, CDCl₃): δ 8.55-8.53 (m, 2H), 7.78-7.56 (m, 2H), 7.50-7.49 (m, 3H), 7.17 (t, J= 8.4 Hz, 2H), 3.75 (s, 3H), 2.67 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.0, 165.6, 164.8, 164.0 (d, J= 249.3 Hz, 1C), 163.2, 162.2, 137.0, 134.2 (2C), 131.2, 130.4 (d, J= 8.6 Hz, 1C), 128.6 (d, J= 9.3 Hz, 1C), 122.8, 115.7 (d, J= 21.8 Hz, 1C), 52.6, 22.9; ¹⁹F NMR (564 MHz, CDCl₃): δ −110.4; HRMS (ESI+) m/z: calcd for C₁₉H₁₆FN₂O₂ [M + H]⁺: 323.1190; found: 323.1194.

Methyl 4-(4-chlorophenyl)-6-methyl-2-phenyl pyrimidine-5-carboxylate (3m):

Colorless oil; 61% yield; IR (KBr) v (cm⁻¹): 3060, 2920, 2848, 1722, 1539, 1489, 1390, 1265, 1171, 1088; ¹H NMR (600 MHz, CDCl₃): δ 8.55-8.53 (m, 2H), 7.71 (d, J= 8.4 Hz, 2H), 7.51-7.50 (m, 3H), 7.47 (d, J= 8.4 Hz, 2H), 3.76 (s, 3H), 2.68 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.8, 165.7, 163.9, 162.2, 136.9, 136.5, 136.4, 131.20, 129.8, 128.8, 128.6, 128.5, 122.4, 52.7, 22.9; HRMS (ESI+) m/z: calcd for C₁₉H₁₆ClN₂O₂ [M + H]⁺: 339.0895; found: 339.0889.

Isopropyl 4-methyl-2,6-diphenylpyrimidine-5-carboxylate (3n):

White solid³⁸; 88% yield; m.p. 81–28 °C (82–84 °C); IR (KBr) v (cm⁻¹): 3060, 3055, 2976, 2920, 2848, 1720, 1583, 1543, 1267, 1174, 1099; ¹H NMR (600 MHz, CDCl₃): δ 8.56-8.54 (m, 2H), 7.77-7.75 (m, 2H), 7.49-7.46 (m, 6H), 5.12 (m, 1H), 2.69 (s, 3H), 1.11 (d, J= 6.0 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃): δ 168.0, 165.2, 163.7, 163.5, 138.3, 137.3, 131.0, 130.0, 128.7, 128.6, 128.5, 128.5, 123.9, 69.7, 22.8, 21.4; HRMS (ESI+) m/z: calcd for C₂₁H₂₁N₂O₂ [M + H]⁺: 333.1598; found: 333.1595.

Ethyl 4-isopropyl-2,6-diphenylpyrimidine-5-carboxylate (3o):

Colorless oil³⁸; 80% yield; IR (KBr) v (cm⁻¹): 3058, 2971, 2922, 2847, 1722, 1587, 1536, 1265, 1174, 1089; ¹H NMR (600 MHz, CDCl₃): δ 8.62-8.60 (m, 2H), 7.77-7.75 (m, 2H), 7.49-7.45 (m, 6H), 4.19 (q, J= 7.2 Hz, 2H), 3.30 (m, 1H), 1.42 (d, J= 6.6 Hz, 6H), 1.06 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 173.0, 168.7, 163.8, 163.6, 138.5, 137.6, 133.9, 133.7, 131.0, 129.9, 128.7, 128.5, 128.5, 122.82, 61.8, 33.4, 22.0, 13.6; HRMS (ESI+) m/z: calcd for C₂₂H₂₃N₂O₂ [M + H]⁺: 347.1754; found: 347.1761.

Methyl 4-methyl-6-phenyl-2-vinylpyrimidine-5-carboxylate (3p):

Colorless oil; 64% yield; IR (KBr) v (cm⁻¹): 3055, 2948, 1726, 1648, 1536, 1251, 1175, 1078; ¹H NMR (400 MHz, CDCl₃): δ 7.69-7.66 (m, 2H), 7.48-7.46 (m, 3H), 7.00-6.90 (m, 1H), 6.78-6.73 (m, 1H), 5.82-5.79 (m, 1H), 3.71 (s, 3H), 2.62 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 169.7, 165.9, 164.4, 161.9, 161.2, 133.8, 130.7, 130.0, 123.9, 121.5, 52.5, 21.0; HRMS (ESI+) m/z: calcd for C₁₅H₁₅N₂O₂ [M + H]⁺: 255.1128; found: 255.1126.

Methyl 4-(4-methoxyphenyl)-6-methyl-2-vinyl pyrimidine-5-carboxylate (3q):

Colorless oil; 58% yield; IR (KBr) v (cm⁻¹): 3059, 2941, 2866, 1723, 1647, 1533, 1246, 1176, 1077; ¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, J= 9.2 Hz, 2H), 6.90 (d, J= 8.8 Hz, 2H), 6.84-6.80 (m, 1H), 6.68-6.63 (m, 1H), 5.72-5.69 (m, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 2.51 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.2, 163.9, 162.4, 161.6, 16 0.3, 135.3, 129.2, 128.9, 123.9, 121.7, 113.1, 54.4, 51.6, 21.7; HRMS (ESI+) m/z: calcd for C₁₆H₁₇N₂O₃ [M + H]⁺: 285.1234; found: 285.1230.

Ethyl 4-(4-methoxyphenyl)-6-methyl-2-vinyl pyrimidine-5-carboxylate (3r):

Colorless oil; 61% yield; IR (KBr) v (cm⁻¹): 3057, 2920, 2865, 1724, 1647, 1536, 1464, 1365, 1252, 1174, 1078; ¹H NMR (400 MHz, CDCl₃): δ 7.67 (d, J= 8.8 Hz, 2H), 6.97 (d, J= 8.8 Hz, 2H), 6.93-6.85 (m, 1H), 6.75-6.74 (m, 1H), 5.80-5.70 (m, 1H), 4.24 (q, J= 7.2 Hz, 2H), 3.86 (s, 3H), 2.60 (s, 3H), 1.15 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.6, 164.8, 162.6, 159.2, 158.8, 136.3, 130.0, 129.3, 123.1, 121.5, 114.4, 61.7, 55.4, 22.7, 13.8; HRMS (ESI+) m/z: calcd for C₁₇H₁₉N₂O₃ [M + H]⁺: 299.1390; found: 299.1395.

6-Methyl-N,2-diphenylpyrimidin-4-amine (5a):

White solid; 84% yield; m.p. 114–116 °C; IR (KBr) v (cm⁻¹): 3377, 3055, 2918, 1606, 1537, 1496, 1446, 1367, 1328, 1192, 1084; ¹H NMR (600 MHz, CDCl₃): δ 8.10-88.0 (m, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.51-7.50 (m, 3H), 7.36 (d, J= 7.8 Hz, 3H), 7.06 (s, 1H), 7.04 (d, J= 7.8 Hz, 1H), 2.49 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.6, 164.7, 160.1, 140.0, 137.4, 130.5, 128.9, 128.8, 127.1, 122.1, 118.9, 108.0, 24.4; HRMS (ESI+) m/z: calcd for C₁₇H₁₆N₃ [M + H]⁺: 262.1339; found: 262.1336.

6-Methyl-2-phenyl-N-(p-tolyl)pyrimidin-4-amine (5b):

White solid; 86% yield; m.p. 79–81 °C; IR (KBr) v (cm⁻¹): 3392, 2917, 2846, 1608, 1543, 1511, 1380, 1300, 1255, 1178, 1084, 1026; ¹H NMR (600 MHz, CDCl₃): δ 8.08-78.0 (m, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.50-7.49 (m, 3H), 7.23 (s, 1H), 7.17 (d, J= 8.4 Hz, 2H), 7.03 (s, 1H), 2.48 (s, 3H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.5, 164.7, 160.3, 137.5, 137.4, 131.6, 130.5, 129.3, 128.7, 127.1, 119.2, 107.7, 24.4, 20.8; HRMS (ESI+) m/z: calcd for C₁₈H₁₈N₃ [M + H]⁺: 276.1495; found: 276.1491.

N-(4-chlorophenyl)-6-methyl-2-phenylpyrimidin-4-amine (5c):

White solid; 87% yield; m.p. 142–144 °C; IR (KBr) v (cm⁻¹): 3346, 3051, 2923, 1609, 1539, 1445, 1379, 1325, 1190, 1081; ¹H NMR (600 MHz, CDCl₃): δ 8.06-48.0 (m, 2H), 7.67 (d, J= 9.0 Hz, 2H), 7.50-7.49 (m, 3H), 7.38 (s, 1H), 7.29 (d, J= 9.0 Hz, 2H), 7.06 (s, 1H), 2.48 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.6, 164.6, 159.9, 138.6, 137.2, 130.6, 128.8, 128.8, 127.1, 126.7, 120.1, 108.3, 24.4; HRMS (ESI+) m/z: calcd for C₁₇H₁₅ClN₃ [M + H]⁺: 296.0949; found: 296.0952.

Supplemental Material

sj-doc-1-chl-10.1177_17475198211067163 – Supplemental material for Palladium-catalyzed Hiyama cross-couplings of pyrimidin-2-yl tosylates with organosilanes

Supplemental material, sj-doc-1-chl-10.1177_17475198211067163 for Palladium-catalyzed Hiyama cross-couplings of pyrimidin-2-yl tosylates with organosilanes by Hai-Peng Gong, Zheng-Jun Quan and Xi-Cun Wang in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (no. 21362031 and 21562036) and special funds for discipline construction of Gansu Agricultural University (GAU-XKJS-2018-121).

ORCID iD

Hai-Peng Gong

Supplemental material

Supplemental material for this article is available online.

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