Metal-free cascade synthesis of unsymmetrical 2-aminopyrimidines from imidazolate enaminones

Abstract

A convenient metal-free synthesis of unsymmetrical 2-aminopyrimidines from imidazolate enaminones has been developed. In this procedure, various structural 2-aminopyrimidines, as well as 4,5-dihydroisoxazol-5-ols and pyrazoles were synthesized in moderate to excellent yields. A plausible mechanism was also proposed for the cascade reaction. This method represents an effective strategy towards the synthesis of unsymmetrical 2-aminopyrimidines.

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Introduction

Pyrimidines are important heterocyclic structural motifs, exist in numerous drug molecules and exhibit a wide range of biological activities, such as antineoplastic,¹ antibacterial,² anti-HIV,³ antiviral⁴ and antitubercular.⁵ As illustrated in Fig. 1, examples of leading commercial drugs based on the pyrimidine scaffold include Imatinib,⁶ Pyrimethamine⁷ and Rosuvastatin.⁸ Moreover, pyrimidines are the essential building blocks in DNA and RNA,⁹ and have also found important application in materials chemistry¹⁰ and agricultural chemistry.¹¹ For these reasons, the development of efficient methodologies for the synthesis of pyrimidines continues to be of great significance.¹²

Fig. 1 Selected pyrimidine-containing drugs.

Conventionally, the most popular approaches to the construction of 2-aminopyrimidine moiety consist of: (a) transition-metal-catalyzed amination of 2-Cl or 2-Br-pyrimidines (Scheme 1a);¹³ or (b) condensation of guanidines with 1,3-dicarbonyl compounds or their synthetic equivalents (Scheme 1b).¹⁴ Nevertheless, methodologies based on transition-metal-catalyzed reactions limits their potential application in the pharmaceutical industry owing to the contamination of heavy metals, while routes based on condensation reactions usually require multistep routes to synthesize the unsymmetrical 2-aminopyrimidines, and considerable disadvantages like harsh reaction conditions or poor functional-group tolerance are associated with these processes.^14a–c Therefore, a practical and efficient method for the synthesis of unsymmetrical 2-aminopyrimidine is still of considerable.

Scheme 1 Strategies for the synthesis of unsymmetrical 2-aminopyrimidine.

Recently, enaminones¹⁵ have emerged as important building blocks for the construction of versatile 1,2,3-triazoles, pyridines, indoles and pyrroles.¹⁶ However, a method for the synthesis of unsymmetrical 2-aminopyrimidines from enaminones with guanidines has not been reported. Herein, we designed a metal-free strategy for the synthesis of 2-aminopyrimidines from imidazolate enaminones via a cascade sequence (Scheme 1c).

Results and discussion

At the outset of the study, the condensation of 3-(1H-imidazol-1-yl)-1,3-diphenylprop-2-en-1-one (E/Z) 1a and guanidine hydrochloride 2a was chosen as a model reaction to screen the reaction parameters (Table 1). To our delight, the desired product 3a was obtained in 35% yield when the cascade reaction was conducted at 60 °C in the presence of 4.0 equiv. K₂CO₃ (based on 1a) in toluene for 12 h (entry 1). The yield was improved to 80% when the transformation was conducted with 1,4-dioxane instead of toluene (entry 2). Further studies focused on screening of versatile base (entries 3–6). In the presence of a medium-strength base, such as Cs₂CO₃ and K₃PO₄, the reaction furnished 3a in 82% and 78%, respectively (entries 3 & 4). Other strong bases, including NaOH and NaO^tBu, provided 3a in acceptable yields (entries 5 & 6). Further investigation showed that this transformation was highly solvent dependent (entries 7–14). The yield was improved to 94% by switching the solvent 1,4-dioxane to DMF, while no deviations were observed between DMF, DMSO and NMP (entries 7–9).

Table 1 Optimization of the reaction conditions^a

Entry	Substrate	Base	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), and base (2.0 mmol) in 3 mL of solvent at 60 °C for 12 h under air.b Isolated yield based on 1a.c n.d. = no detected. DMF = N,N-dimethylformamide, DMSO = dimethyl-sulfoxide, NMP = 1-methylpyrrolidin-2-one, DCE = 1,2-dichloroethane, THF = tetrahydrofuran.
1	1a	K2CO3	Toluene	35
2	1a	K2CO3	1,4-Dioxane	80
3	1a	Cs2CO3	1,4-Dioxane	82
4	1a	K3PO4	1,4-Dioxane	78
5	1a	NaOH	1,4-Dioxane	42
6	1a	NaO^tBu	1,4-Dioxane	36
7	1a	K2CO3	DMF	94
8	1a	K2CO3	DMSO	92
9	1a	K2CO3	NMP	89
10	1a	K2CO3	EtOH	60
11	1a	K2CO3	CH3CN	56
12	1a	K2CO3	THF	42
13	1a	K2CO3	DCE	38
14	1a	K2CO3	H2O	n.d.^c
15	A	K2CO3	DMF	92
16	B	K2CO3	DMF	89
17	C	K2CO3	DMF	79
18	D	K2CO3	DMF	85
19	E	K2CO3	DMF	83
20	F	K2CO3	DMF	87
21	G	K2CO3	DMF	54

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However, other solvents, such as EtOH, CH₃CN, THF, DCE and H₂O led to no reaction or lower yield (entries 10–14). When other enaminones A–G were subjected to the metal-free cascade reaction, the desired product 3a could also be successfully attained, albeit in decreased yields (entries 15–21). On the basis of the above results, the optimized conditions for the reaction comprise the base by 4.0 equiv. K₂CO₃ at 60 °C in DMF to furnish the single 2-aminopyrimidine 3a in 94% yield (Table 1, entry 7).

With the optimized reaction conditions in hand, the generality and scope of the metal-free cascade reactions were investigated as illustrated in Table 2. Interestingly, a wide range of substrates were well tolerated under the cascade reaction conditions, affording the corresponding unsymmetrical 2-aminopyrimidines (3a–3u) in 58–96% yields. Generally, imidazolate enaminones with electron-donating substituents (–Me, –n-Bu & –OMe) (entries 2–9) provided the corresponding products in higher yields than those bearing electron-withdrawing groups (–F, –Cl, –Br, –CN & –COOMe) (entries 10–18). As for regioisomeric substrates, imidazolate enaminones with substituents in Ar-R¹ (entries 2, 6, 10 & 15) could be transformed into the corresponding 2-aminopyrimidines products in similar yields as those with substituents in Ar-R² (entries 3, 7, 11 & 16). A significant influence of steric hindrance on this reaction was observed. For instance, the ortho-substituted substrates led to lower yield than the para-substituted substrates (entries 2 & 5, 10 & 12). Notably, alkyl enaminones with cyclopropyl or t-butyl could also participate in this reaction, albeit giving lower yield of the product (entries 19, 20 & 21). Moreover, imidazolate enaminones possessing thiophenyl and naphthyl ring were also tested (entries 22, 23 & 24). Additionally, other representative guanidine analogues, such as benzimidamide 1,1-dimethylguanidine, were well-tolerated (entries 25 & 26).

Table 2 Scope of substrates^a

Entry			Yield^b (%)
a Under the optimized conditions.b Isolated yield.c Reaction performed at 10 mmol scale.
1	R^1 = H, R^2 = H, 1a	3a	94 (90)^c
2	R^1 = 4-Me, R^2 = H, 1b	3b	95
3	R^1 = H, R^2 = 4-Me, 1b′		92
4	R^1 = 3-Me, R^2 = H, 1c	3c	90
5	R^1 = 2-Me, R^2 = H, 1d	3d	80
6	R^1 = 4-OMe, R^2 = H, 1e	3e	96
7	R^1 = H, R^2 = 4-OMe, 1e′		92
8	R^1 = 3-OMe, R^2 = H, 1f	3f	88
9	R^1 = H, R^2 = 4-n-Bu, 1g	3g	90
10	R^1 = 4-F, R^2 = H, 1h	3h	80
11	R^1 = H, R^2 = 4-F, 1h′		78
12	R^1 = 2-F, R^2 = H, 1i	3i	63
13	R^1 = 3-Cl, R^2 = H, 1j	3j	81
14	R^1 = H, R^2 = 4-Cl, 1k	3k	80
15	R^1 = 4-Br, R^2 = H, 1l	3l	81
16	R^1 = H, R^2 = 4-Br, 1l′		77
17	R^1 = 4-CN, R^2 = H, 1m	3m	75
18	R^1 = H, R^2 = 4-COOMe, 1n	3n	72
19			66
20			58
21			72
22			65
23			60
24			96
25	1a		88
26	1a		90

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Subsequently, hydroxylamine hydrochloride 2b and hydrazine hydrate 2c were also tolerated in the cascade reaction system and furnished the product 3,5-diphenyl-4,5-dihydroisoxazol-5-ol 3ab and 3,5-diphenyl-1H-pyrazole 3ac in 91% and 96% yields, respectively (Scheme 2a and b).¹⁷ However, when imidazolate enaminones 1e′ and 1e involved to react with hydroxylamine hydrochloride 2b and phenylhydrazine 2d, the single products 4,5-dihydroisoxazol-5-ol 3e′b and pyrazole 3ed were obtained in 75% and 82% yields, respectively (Scheme 2c and d).¹⁷ It's suggested that the imidazole is replaced by hydroxylamine or hydrazine in the first step of the reaction, while the condensations of hydroxylamine or hydrazine with the carbonyl group do not occurs.

Scheme 2 The synthesis of isoxazole and pyrazole.

Base on the above results, the mechanistic pathways of this cascade metathesis were proposed and presented in Scheme 3. The initial step of the reaction involved the formation of intermediate H from 3-(1H-imidazol-1-yl)-1,3-diphenylprop-2-en-1-one (E/Z) 1a via the substitution procedure followed by the released one molecular of imidazole (path a). Conversely, the condensation of carbonyl group with guanidine was not observed in the first step of the reaction (path b). Then thermally inducing the transformation of intermediate H gave the desired unsymmetrical 2-aminopyrimidine 3a.

Scheme 3 Plausible mechanism.

Conclusions

In conclusion, we have developed a convenient metal-free method for the synthesis of unsymmetrical 2-aminopyrimidines from imidazolate enaminones and guanidine hydrochloride. Imidazolate enaminones with electron-donating and electron-withdrawing groups provided 2-aminopyrimidines in moderate-to-excellent yields. The steric effect on this reaction was also observed. Moreover, the plausible mechanism was proposed base on the synthesis of 5-hydroxy-4,5-dihydroisoxazoles and pyrazoles in the cascade reaction system. This method represents an effective strategy towards the synthesis of unsymmetrical 2-aminopyrimidines.

Experimental

General information

Unless otherwise stated, all reagents were used directly without further purification. Silica gel was purchased from Qing Dao Hai Yang Chemical Industry Co. All melting points were determined on a Beijing Science Instrument Dianguang Instrument Factory XT4B melting point apparatus and uncorrected. ¹H and ¹³C NMR spectra were measured on a 400 MHz Bruker spectrometer (¹H 400 MHz, ¹³C100 MHz), using CDCl₃ as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. HRMS-ESI spectra were equipped with an ESI source and a TOF detector. PE is petroleum ether (60–90 °C).

Typical procedure for the preparation of 4,6-diphenylpyrimidin-2-amine (3a)

A suspension of 3-(1H-imidazol-1-yl)-1,3-diphenylprop-2-en-1-one (E/Z) 1a (0.5 mmol, 137.0 mg), guanidine hydrochloride 2 (1.0 mmol, 95.5 mg) and K₂CO₃ (2.0 mmol, 276.4 mg) in DMF (3 mL) was stirred at 60 °C for 12 h. After 1a was exhausted completely (monitored by TLC), it was cooled down to room temperature and saturated aqueous brine (10 mL) was added. The mixture was stirred for 10 min and then was extracted by EtOAc (3 × 10 mL). The combined organic layers were dried over Na₂SO₄. After filtration, removal of the solvent gave a residue, which was purified by a column chromatography (silica gel, PE/EtOAc = 5/1) to afford 3a as light yellow solid; 116 mg, 94% yield; mp 118–120 °C (lit.¹² 118 °C). IR (KBr) ν 3307, 3192, 1629, 1365, 763 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 4H), 7.52–7.46 (m, 7H), 5.24 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 163.6, 137.8, 130.4, 128.8, 127.1, 104.3.

A similar procedure was used for the preparation of products 3b–3t & 3ab–3ed

4-Phenyl-6-(p-tolyl)pyrimidin-2-amine (3b). 124 mg from 1b, 95% yield; 120 mg from 1b′, 92% yield; yellow solid, mp 125–127 °C (lit.¹² 128 °C). IR (KBr) ν 3314, 3202, 1569, 1365, 770 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.49 (m, 3H), 7.45 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 5.22 (s, 2H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.1, 166.1, 163.6, 140.8, 137.9, 134.9, 130.4, 129.5, 128.7, 127.1, 127.0, 104.0, 21.4.

4-Phenyl-6-(m-tolyl)pyrimidin-2-amine (3c). 118 mg, 90% yield; yellow liquid, mp 134–138 °C. IR (KBr) ν 3309, 3186, 1635, 1366, 768 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 2H), 7.87 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.49 (m, 3H), 7.44 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 166.1, 163.6, 138.4, 137.8, 137.7, 131.2, 130.4, 128.7, 128.6, 127.7, 127.1, 124.2, 104.4, 21.5. HRMS m/z (ESI) calcd for C₁₇H₁₅N₃, (M + Na)⁺ 284.1158; found, 284.1159.

4-Phenyl-6-(o-tolyl)pyrimidin-2-amine (3d). 105 mg, 80% yield; white solid, mp 134–136 °C. IR (KBr) ν 3299, 3186, 1629, 1356, 764 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.02 (m, 2H), 7.49–7.43 (m, 4H), 7.36–7.28 (m, 3H), 7.15 (s, 1H), 5.30 (s, 2H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.3, 165.6, 163.2, 138.9, 137.5, 135.7, 130.9, 130.5, 129.1, 128.9, 128.8, 127.1, 126.0, 108.0, 20.2. HRMS m/z (ESI) calcd for C₁₇H₁₅N₃, (M + Na)⁺ 284.1158; found, 284.1160.

4-(4-Methoxyphenyl)-6-phenylpyrimidin-2-amine (3e). 133 mg from 1e, 96% yield; 127 mg from 1e′, 92% yield; pink solid, mp 150–152 °C (lit.¹² 152 °C). IR (KBr) ν 3326, 3196, 1538, 1361, 822 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 8.0 Hz, 4H), 7.49 (m, 3H), 7.41 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.24 (s, 2H), 3.87 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 165.6, 163.5, 161.6, 137.9, 130.3, 130.1, 128.7, 128.6, 127.1, 114.1, 103.5, 55.4.

4-(3-Methoxyphenyl)-6-phenylpyrimidin-2-amine (3f). 122 mg, 88% yield; yellow solid, mp 136–138 °C (lit.¹² 139–140 °C). IR (KBr) ν 3450, 3314, 1567, 1356, 768 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 2H), 7.62 (m, 2H), 7.53–7.38 (m, 5H), 7.03 (m, 1H), 5.29 (s, 2H), 3.90 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.3, 166.0, 163.6, 160.0, 139.2, 137.7, 130.5, 129.8, 128.8, 127.1, 119.5, 116.4, 112.2, 104.4, 55.4.

4-(4-Butylphenyl)-6-phenylpyrimidin-2-amine (3g). 136 mg, 90% yield; yellow solid, mp 90–94 °C. IR (KBr) ν 2957, 1565, 1531, 1364, 768 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 2H), 7.98 (d, J = 12.0 Hz, 2H), 7.51–7.45 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 5.22 (s, 2H), 2.68 (t, J = 8.0 Hz, 2H), 1.64 (m, 2H), 1.38 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.3, 166.1, 163.6, 145.8, 137.9, 135.1, 130.4, 128.9, 128.7, 127.1, 127.0, 104.1, 35.5, 33.5, 22.3, 13.9. HRMS m/z (ESI) calcd for C₂₀H₂₁N₃, (M + Na)⁺ 326.1628; found, 326.1630.

4-(4-Fluorophenyl)-6-phenylpyrimidin-2-amine (3h). 106 mg from 1h, 80% yield; 103 mg from 1h′, 78% yield; white solid, mp 130–132 °C (lit.¹² 132 °C). IR (KBr) ν 3333, 3207, 1639, 1228, 768 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.09–8.04 (m, 4H), 7.50 (t, J = 4.0 Hz, 3H), 7.42 (s, 1H), 7.18 (t, J = 8.0 Hz, J = 12.0 Hz, 2H), 5.23 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 165.6, 164.4 (d, J = 249.0 Hz), 163.5, 137.6, 133.8 (d, J = 3.0 Hz), 130.5, 129.1 (d, J = 8.0 Hz), 128.8, 127.1, 115.8 (d, J = 1.0 Hz), 103.9.

4-(2-Fluorophenyl)-6-phenylpyrimidin-2-amine (3i). 84 mg, 63% yield; yellow solid, mp 123–126 °C. IR (KBr) ν 3323, 1630, 1358, 759 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 3H), 7.56 (d, J = 4.0 Hz, 1H), 7.50–7.42 (m, 4H), 7.29 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.0 Hz, J = 8.0 Hz, 1H), 5.22 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.1, 163.5, 162.1 (d, J = 2.0 Hz), 161.1 (d, J = 250.0 Hz), 137.6, 131.6 (d, J = 9.0 Hz), 130.6 (d, J = 2.0 Hz), 130.5, 128.8, 127.2, 125.9 (d, J = 11.0 Hz), 124.5 (d, J = 4.0 Hz), 116.4 (d, J = 23.0 Hz), 108.3 (d, J = 11.0 Hz). HRMS m/z (ESI) calcd for C₁₆H₁₂FN₃, (M + Na)⁺ 288.0907; found, 288.0909.

4-(3-Chlorophenyl)-6-phenylpyrimidin-2-amine (3j). 114 mg, 81% yield; white solid, mp 118–120 °C (lit.¹² 118 °C). IR (KBr) ν 3486, 3320, 1638, 1360, 771 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.06–8.01 (m, 3H), 7.92 (d, J = 8.0 Hz, 2H), 7.54–7.38 (m, 6H), 5.54 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 146.7, 163.7, 139.6, 137.6, 134.9, 130.7, 130.4, 130.1, 128.9 (2C), 127.4, 127.2 (2C), 125.3, 104.2.

4-(4-Chlorophenyl)-6-phenylpyrimidin-2-amine (3k). 112 mg, 80% yield; yellow solid, mp 158–160 °C (lit.¹² 160 °C). IR (KBr) ν 3318, 3195, 1634, 1360, 768 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.06–8.00 (m, 4H), 7.51–7.45 (m, 5H), 7.42 (s, 1H), 5.26 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 164.9, 163.6, 137.6, 136.6, 136.1, 130.6, 129.0, 128.8, 128.4, 127.1, 103.9.

4-(4-Bromophenyl)-6-phenylpyrimidin-2-amine (3l). 132 mg from 1l, 81% yield; 126 mg from 1l′, 77% yield; yellow solid, mp 170–174 °C (lit.¹² 171–172 °C). IR (KBr) ν 3302, 3192, 1633, 1360, 765 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (m, 2H), 7.95 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.50 (m, 3H), 7.43 (s, 1H), 5.20 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 164.9, 163.6, 137.6, 136.6, 131.9, 130.6, 128.8, 128.6, 127.1, 125.0, 103.9.

4-(2-Amino-6-phenylpyrimidin-4-yl)benzonitrile (3m). 102 mg, 75% yield; white solid, mp 184–186 °C. IR (KBr) ν 3469, 3119, 2322, 1612, 767 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 8.0 Hz, 2H), 8.06–8.03 (m, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.53–7.49 (m, 3H), 7.45 (s, 1H), 5.40 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 164.0, 163.8, 142.0, 137.3, 132.6 (2C), 130.9, 129.0 (2C), 127.8 (2C), 127.2 (2C), 118.6, 113.9, 104.5. HRMS m/z (ESI) calcd for C₁₇H₁₂N₄, (M + Na)⁺ 295.0954; found, 295.0951.

Methyl 4-(2-amino-6-phenylpyrimidin-4-yl)benzoate (3n). 110 mg, 72% yield; light yellow solid, mp 156–158 °C. IR (KBr) ν 3386, 3103, 1645, 762 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.16–8.03 (m, 6H), 7.50–7.46 (m, 4H), 5.47 (s, 2H), 3.94 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.8, 165.7, 164.0, 162.8, 140.9, 136.5, 130.7, 129.7, 129.1 (2C), 127.9 (2C), 126.24 (2C), 126.19 (2C), 103.6, 51.4. HRMS m/z (ESI) calcd for C₁₈H₁₅N₃O₂, (M + Na)⁺ 328.1056; found, 328.1058.

4-Cyclopropyl-6-phenylpyrimidin-2-amine (3o). 70 mg from 1o, 66% yield; 61 mg from 1o′, 58% yield; white solid, mp 122–126 °C. IR (KBr) ν 2968, 1523, 1510, 1346, 770 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.94 (m, 2H), 7.45 (t, J = 4.0 Hz, 3H), 6.88 (s, 1H), 5.16 (s, 2H), 1.94–1.88 (m, 1H), 1.12–1.08 (m, 2H), 1.03–0.98 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 173.5, 164.5, 163.3, 137.7, 130.1, 128.6 (2C), 127.0 (2C), 105.5, 29.6, 17.0, 10.1. HRMS m/z (ESI) calcd for C₁₃H₁₃N₃, (M + Na)⁺ 234.1002; found, 234.1000.

4-(tert-Butyl)-6-phenylpyrimidin-2-amine (3p). 82 mg, 72% yield; yellow solid, mp 98–102 °C. IR (KBr) ν 2937, 1545, 1503, 1388, 778 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.98–7.95 (m, 2H), 7.48–7.45 (m, 3H), 7.06 (s, 1H), 5.23 (s, 2H), 1.34 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 179.7, 165.6, 163.1, 138.2, 130.1, 128.6 (2C), 127.0 (2C), 103.4, 37.3, 29.3 (3C). HRMS m/z (ESI) calcd for C₁₃H₁₃N₃, (M + Na)⁺ 250.1315; found, 250.1317.

4-Phenyl-6-(thiophen-2-yl)pyrimidin-2-amine (3q). 84 mg, 65% yield; yellow solid, mp 137–140 °C (lit.¹² 208–210 °C). IR (KBr) ν 3448, 3320, 1580, 1346, 769 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.05–8.00 (m, 2H), 7.78 (d, J = 4.0 Hz, 1H), 7.51–7.47 (m, 4H), 7.36 (s, 1H), 7.15 (t, J = 4.0 Hz, 1H), 5.32 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 163.5, 160.7, 143.2, 137.7, 130.6, 129.3, 128.9 (2C), 128.3, 127.2 (2C), 127.1, 102.6.

4-Phenyl-6-(thiophen-3-yl)pyrimidin-2-amine (3r). 76 mg, 60% yield; yellow solid, mp 114–116 °C (lit.¹² 113–115 °C). IR (KBr) ν 3432, 3347, 1568, 1376, 770 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 4.0 Hz, 1H), 8.05–8.01 (m, 2H), 7.69–7.78 (d, J = 4.0 Hz, 1H), 7.51–7.47 (m, 3H), 7.41 (t, J = 4.0 Hz, 1H), 7.33 (s, 1H), 5.35 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 163.7, 161.7, 140.8, 137.8, 130.6, 128.9 (2C), 127.2 (2C), 126.6, 126.3, 126.3, 104.2.

4-(Naphthalen-2-yl)-6-phenylpyrimidin-2-amine (3s). 142 mg, 96% yield; yellow solid, mp 115–118 °C (lit.¹² 113–115 °C). IR (KBr) ν 3328, 3208, 1645, 805 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.18–8.09 (m, 3H), 7.99–7.88 (m, 3H), 7.59 (s, 1H), 7.55–7.51 (m, 5H), 5.48 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 166.2, 163.8, 137.9, 135.1, 134.5, 133.3, 130.6, 129.0, 128.9 (2C), 128.6, 127.8, 127.3 (2C), 127.2, 126.6, 124.3, 104.6.

2,4,6-Triphenylpyrimidine (3t). 136 mg, 88% yield; yellow solid, mp 186–188 °C. IR (KBr) ν 2858, 1559, 1354, 760 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J = 8.0 Hz, 2H), 8.31 (d, J = 8.0 Hz, 4H), 8.02 (s, 1H), 7.60–7.53 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.7, 164.5, 138.1, 137.5, 130.8, 130.6, 128.9, 128.5, 128.4, 127.3, 110.3.

N,N-Dimethyl-4,6-diphenylpyrimidin-2-amine (3u). 124 mg, 90% yield; yellow solid, mp 124–126 °C. IR (KBr) ν 3325, 1632, 1363, 766 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.14 (m, 4H), 7.52–7.46 (m, 6H), 7.37 (s, 1H), 3.36 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 165.0, 162.9, 138.5, 130.2, 128.6, 127.1, 101.0, 37.0. HRMS m/z (ESI) calcd for C₁₈H₁₇N₃, (M + Na)⁺ 298.1315; found, 298.1317.

3,5-Diphenyl-4,5-dihydroisoxazol-5-ol (3ab). 102 mg, 86% yield; white solid, mp 163–165 °C (lit.¹⁷ 161–163 °C). IR (KBr) ν 3378, 3298, 1597, 1363, 761 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.71–7.65 (m, 4H), 7.44–7.38 (m, 6H), 3.68 (d, J = 20.0 Hz, 1H), 3.49 (d, J = 16.0 Hz, 1H), 3.20 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 157.4, 140.7, 130.4, 129.2, 129.0, 128.8, 128.6, 126.8, 125.6, 107.7, 49.0.

3,5-Diphenyl-1H-pyrazole (3ac). 99 mg, 90% yield; white solid, mp 198–200 °C (lit.¹⁷ 201–203 °C). IR (KBr) ν 2830, 1461, 685 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 7.72 (d, J = 8.0 Hz, 4H), 7.41–7.37 (m, 4H), 7.35–7.31 (m, 2H), 6.83 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 128.9, 128.2, 125.6, 100.1.

3-(4-Methoxyphenyl)-5-phenyl-4,5-dihydroisoxazol-5-ol (3e′b). 101 mg, 75% yield; white solid, mp 130–132 °C (lit.¹⁷ 130–132 °C). IR (KBr) ν 3369, 3300, 1611, 1373, 775 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.64 (m, 4H), 7.39 (m, 3H), 6.92 (d, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 16.0 Hz, 1H), 3.46 (d, J = 16.0 Hz, 1H), 3.26 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 161.3, 157.0, 140.8, 128.9, 128.5 (2C), 128.3 (2C), 125.6 (2C), 121.8, 114.2 (2C), 107.4, 55.4, 49.2.

5-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole (3ed). 133 mg, 82% yield; white solid, mp 78–80 °C (lit.¹⁷ 77–79 °C). IR (KBr) ν 2826, 1458, 676 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 8.0 Hz, 2H), 7.47–7.31 (m, 8H), 7.22 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.79 (s, 1H), 3.81 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 159.5, 151.8, 144.2, 140.2, 133.1, 130.0 (2C), 128.8 (2C), 128.6 (2C), 127.9, 127.3, 125.7 (2C), 125.2 (2C), 122.9, 113.9, 104.6, 55.2.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by Hainan Provincial Nature Science Foundation of China (Nos. 820QN264 & 2019RC214) and Fundamental Research Funds of Hainan Medical University (No. XRC180009).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra04319f

‡ X. Cui and J. Ma contributed equally to this work.

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