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Abstract

A three-step synthesis of 2-arylamino-5-formyl-pyrimidines is developed by condensation of the bis(hexafluorophosphate) Arnold salt with N-arylguanidines. This method conveniently provides the corresponding 2-arylaminopyrimidine derivatives in good yields.

Keywords

annulation Arnold salt guanidines pyrimidines triformylmethane

Introduction

The Arnold salt is the only practical source of triformylmethane known to date, which was first isolated by Arnold as the perbromide salt 1a and perchlorate salt 1b (Figure 1).^1,2 Afterwards, other Arnold salts were prepared and reported, including tetrafluoroborate salt 1c,^3,4 hexafluorophosphate salt 1d and mixed chlorine/bromine trihalide salts.^5,6 These dimethylaminomethylene vinamidinium salts can serve as important three-carbon building blocks for preparing a wide array of carbocycles and heterocycles.⁷ 2-Arylaminopyrimidines are found in many biologically active natural products and also serve as components of a number of prominent commercial drugs, such as imatinib, nilotinib, pazopanib and rilpivirine (Figure 2).^8–11 Not surprisingly, the synthesis of these building blocks is an attractive subject in organic chemistry. Although the previously published approach to access 2,5-disubstituted pyrimidines involved the condensation of Arnold salts with appropriate nucleophiles, the most widely used Arnold salt was the perchlorate salt 1b,¹² a high-energy material with significant shock sensitivity.¹³ Although the tetrafluoroborate salt 1c, a safer Arnold salt, was used by Ragan to prepare a variety of 2,5-disubstituted pyrimidines,¹⁴ it was hygroscopic and thus not very convenient to handle. Moreover, in the published synthesis of 2,5-disubstituted pyrimidines, the nucleophiles were mainly amidines and a few N-alkylguanidines,¹⁵ while the condensation of Arnold salts with N-aryl-guanidines to afford 2-arylaminopyrimidines has scarcely been reported.

Figure 1.

Some typical Arnold salts.

Figure 2.

Examples of drugs with 2-arylaminopyrimidine moieties.

Since bis(hexafluorophosphate) Arnold salt 1d is a safe and non-hygroscopic material with a well-determined molecular weight, this Arnold salt should be an attractive alternative. Curiously, the literature reports about the use of in salt 1d heterocycle synthesis and its thermal analysis are very scarce.^14,16 To further explore the potential utility of this bis(hexafluorophosphate) Arnold salt 1d, we investigated its condensation with a series of N-arylguanidines. As a result, some interesting pyrimidine derivatives have been synthesized in moderate to good yields. Herein, we report the details of our investigations.

Results and discussion

Our synthesis of bis(hexafluorophosphate) salt 1d was through a slightly modified process, using inexpensive malonic acid as the starting material instead of the irritant bromoacetic acid.¹⁷ After carbon dioxide evolution had ceased, aqueous ammonium hexafluorophosphate was added to the mixture to precipitate the corresponding vinamidinium salt (Scheme 1). As far as we know, the differential scanning calorimetry (DSC) analysis of 1d has not been reported before. Thus, the DSC analysis of 1d was first tested and the result showed that its energy was 257 J/g. This result confirmed that the hexafluorophosphate salt should be very stable.

Scheme 1.

Our synthesis of 1d.

With the desired salt in hand, we attempted to prepare an array of N-arylguanidines. The direct coupling of aromatic amines with cyanamide under acidic conditions is a straightforward method to prepare N-arylguanidines. However, this protocol was not appealing since the resulting crude products were difficult to purify and the yields were fairly low with significant qualities of aromatic amines recovered. Thus, a two-step method was adopted. Aromatic amines 2a–k were first treated with N,N′-bis-Boc-1H-pyrazole-1-carboxamidine (3) to give bis-Boc guanidines 4a–h, which were deprotected under acidic conditions to afford the desired products 5a–h (Table 1). Generally, the yields of the bis-Boc guanidines were good. However, the reactions with 2-chloro-6-methyl-phenylamine (2i), 4-nitro-aniline (2j) and 4-trifluoromethylphenylamine (2k) failed to give the desired products (Table 1, entries 9–11), with only the starting materials being recovered. This suggested that steric and electronic effects played crucial roles in this substitution reaction. Both steric hindrance and the presence of electron-withdrawing groups dramatically reduced the nucleophilicity of these anilines.

Table 1.

The structures and yields of compounds 4 and 5.^a


Entry	R	Product 4	Yield (%)^b	Product 5	Yield (%)^b
1	H	4a	84	5a	85
2	4-F	4b	87	5b	80
3	4-CH₃	4c	85	5c	68
4	2-CH₃, 4-Br	4d	68	5d	68
5	3-Cl	4e	78	5e	65
6	4-Cl	4f	87	5f	87
7	4-CH₃O	4g	89	5g	85
8	H (2-naphthylamine)	4h	85	5h	83
9	2-Cl-6-CH₃	4i	–	5i	NA
10	4-NO₂	4j	–	5j	NA
11	4-CF₃	4k	–	5k	NA

TFA: trifluoroacetic acid; –: no product obtained; NA: not available.

Reagents and conditions: a mixture of 2a–k and 3 in chloroform was refluxed for 5 h (for the first step); a mixture of 4a–h in TFA and dichloromethane was stirred at room temperature for 4 h (for the second step).

Isolated yield.

Subsequently, the condensation of Arnold salt 1d with guanidine 5a was used to screen for the reaction conditions (Table 2). Among the three bases screened, potassium carbonate gave an excellent yield (Table 2, entry 3). Sodium carbonate was also good, but the reaction time was longer (Table 2, entry 4). Sodium bicarbonate, a weaker base, also afforded the product in a good yield (Table 2, entry 5). However, if no base was added, the reaction did not occur (Table 2, entry 1). The effect of solvents was also explored. It was found that a mixture of methanol and water gave good yields (Table 2, entries 3–5), while pure methanol did not yield the product (Table 2, entry 2). The use of a protic solvent dimethylformamide (DMF) produced 6a, but the reaction time was much longer and the yield was decreased. With the protocol in hand, the remaining guanidines 5b–h were condensed with Arnold salt 1d using potassium carbonate as base in a mixture of methanol and water. The reactions proceeded smoothly, and the yields of the desired products were good to excellent (Table 3).

Table 2.

Effect of bases and solvents on the condensation.^a


Entry	Base	Solvent	Time (h)	Yield (%)^b
1	None	CH₃OH/H₂O^c	3	–
2	K₂CO₃	CH₃OH	5	–
3	K₂CO₃	CH₃OH/H₂O^c	3	92
4	Na₂CO₃	CH₃OH/H₂O^c	5	90
5	NaHCO₃	CH₃OH/H₂O^c	6	80
6	K₂CO₃	CH₃OH	5	85
7	K₂CO₃	DMF	5	81

DMF: dimethylformamide; –: no product obtained.

Reagents and conditions: a mixture of 5a, 1d and the base (except for entry 1) in solvent was stirred at 50°C.

Isolated yield.

Methanol:water = 3:1.

Table 3.

Synthesis of 2-arylamino-5-formyl-pyrimidines.^a


Entry	R	Time (h)	Product	Yield (%)^b
1	H	6	6a	92
2	4-F	5	6b	87
3	4-CH₃	12	6c	90
4	2-CH₃, 4-Br	12	6d	83
5	3-Cl	4.5	6e	81
6	4-Cl	7	6f	80
7	4-CH₃O	12	6g	90
8	H (2-naphthylamine)	12	6h	88

Reagents and conditions: a mixture of 5a–h and 1d in methanol and water was stirred at 50°C for 6 h.

Isolated yield.

Conclusion

In conclusion, the condensation of N-arylguanidines with bis(hexafluorophosphate) Arnold salt 1d is a facile method for the synthesis of N-arylpyrimidines. This method is convenient and the overall yields were generally good.

Experimental

Commercial reagents were used without further purification. Melting points were measured on a SGW X-4 (INESA) melting point apparatus and are uncorrected. ¹H NMR spectra were recorded on Bruker DRX-500 (500 MHz) or DRX-600 (600 MHz) instrument. ¹³C NMR spectra were obtained on JNMEX400 (125 MHz) or JNMEX400 (150 MHz) instrument. Mass spectra (MS) were recorded on a Bruker MicrOTOF II mass spectrometer or a Waters High Resolution UPLCTOFMS spectrometer. Infrared (IR) spectra were obtained using attenuated total reflectance (ATR) on a Fourier transform infrared (FTIR) Bruker Tensor 27. DSC was determined on a Mettler Toledo TGA/DSC 3+.

General procedure for the synthesis of Arnold salt 1d

Synthesis of bis(hexafluorophosphate) Arnold salt (1d)

Trichlorophosphate (73 g, 0.48 mol) was added dropwise to DMF (63.3 g, 0.87 mol) at 0°C. Next, malonic acid (15 g, 0.14 mol) was added and the resulting mixture was stirred at 90 °C for 7 h. NH₄PF₆ (47 g, 0.29 mol) was dissolved in ice water and added to the reaction mixture. The Arnold salt precipitated and was triturated with isopropanol (120 mL) to give pure 1d as a light yellow solid: Yield 43.7 g (64%); m.p. 200–203°C; ¹H NMR (CD₃CN, 500 MHz): δ = 8.01 (s, 3H), 3.52 (s, 9H), 3.38 (s, 9H); ¹³C NMR (CD₃CN, 125 MHz): δ = 164.4, 90.8, 49.1, 43.2.

General procedure for the synthesis of bis-Boc guanidines

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-4-benzene (4a)

N,N′-bis-Boc-1H-pyrazole-1-carboxamidine (3) (1.0 g, 3.22 mol) and aniline 2a (0.39 g, 4.23 mmol) were dissolved in CHCl₃ (5 mL). The resulting mixture was stirred for 5 h at 50°C. The organic phase was washed with 1 M HCl solution (5 mL), dried and evaporated to give the crude product. The residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4a as a colourless solid¹⁸: Yield 0.91 g (84%); m.p. 128–130°C (lit. 129–132°C); ¹H NMR (CDCl₃, 500 MHz): δ = 11.67 (s, 1H), 10.36 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 1.56 (s, 9H), 1.53 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 153.5, 153.3, 136.7, 128.8, 124.7, 122.1, 83.7, 79.7, 28.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₆N₃O₄: 336.1918; found: 336.1917.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-4-fluorobenzene (4b)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4b as a colourless solid: Yield 0.99 g (87%); m.p. 135–137°C; ¹H NMR (CDCl₃, 500 MHz): δ = 11.65 (s, 1H), 10.31 (s, 1H), 7.56–7.59 (m, 2H), 7.04 (t, J = 8.6 Hz, 2H), 1.56 (s, 9H), 1.52 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 153.4, 153.3, 138.0, 134.4, 129.8, 124.7, 121.1 (d, J = 241.3 Hz), 84.0, 79.9, 28.1, 28.0; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₇H₂₅FN₃O₄: 354.1824; found: 354.1818; IR: 2998, 1716, 1494, 1305 cm⁻¹.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-4-methylbenzene (4c)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4c as a colourless solid¹⁹: Yield 0.96 g (85%); m.p. 120–122°C (lit. 120–122°C); ¹H NMR (CDCl₃, 500 MHz): δ = 11.68 (s, 1H), 10.28 (s, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H), 1.56 (s, 9H), 1.52 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 163.4, 153.5, 153.3, 134.4, 134.1, 129.3, 122.2, 83.6, 79.5, 28.2, 28.1, 20.9; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₈H₂₈N₃O₄: 350.2074; found: 350.2070.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-2-methyl-4-bromobenzene (4d)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4d as a colourless solid: Yield 0.94 g (68%); m.p. 161–164°C; ¹H NMR (CDCl₃, 500 MHz): δ = 11.69 (s, 1H), 10.19 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.28–7.36 (m, 2H), 2.30 (s, 3H), 1.56 (s, 9H), 1.50 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 153.7, 153.4, 134.3, 132.9, 132.1, 129.5, 125.7, 118.0, 83.8, 79.8, 28.1, 28.0, 17.9; HRMS (ESI) m/z [M (⁷⁹Br)]⁺ calcd for C₁₈H₂₇BrN₃O₄: 428.1179; [M (⁸¹Br)]⁺: 430.1159; found: 428.1173; 430.1154; IR: 2983, 1708, 1487, 1305 cm⁻¹.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-3-chlorobenzene (4e)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4e as a colourless solid: Yield 0.93 g (78%); m.p. 145–148°C; ¹H NMR (CDCl₃, 500 MHz): δ = 11.64 (s, 1H), 10.41 (s, 1H), 7.70 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.13–7.08 (m, 1H), 1.56 (s, 9H), 1.53 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 160.7, 158.8, 153.6, 153.3, 132.7, 124.0, 123.9, 115.6, 115.4, 83.8, 79.7, 28.1, 28.0; HRMS (ESI) m/z [M (³⁵Cl) + H]⁺ calcd for C₁₇H₂₅ClN₃O₄: 370.1528; [M (³⁷Cl) + H]⁺: 372.1499; found: 370.1522; 372.1498; IR: 2893, 1708, 1487, 1297, 759 cm⁻¹.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-4-chlorobenzene (4f)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4f as a colourless solid²⁰: Yield 1.04 g (87%); m.p. 141–144°C; ¹H NMR (CDCl₃, 500 MHz): δ = 11.64 (s, 1H), 10.37 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.3–7.29 (m, 2H), 1.56 (s, 9H), 1.53 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 153.4, 153.3, 135.4, 129.8, 128.9, 123.3, 83.9, 79.9, 28.1, 28.0; HRMS (ESI) m/z [M (³⁵Cl) + H]⁺ calcd for C₁₇H₂₅ClN₃O₄: 370.1528; [M (³⁷Cl) + H]⁺: 372.1499; found: 370.1534; 372.1507.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-4-methoxybenzene (4g)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4g as a colourless solid: Yield 1.05 g (89%); m.p. 115–116°C; ¹H NMR (CDCl₃, 500 MHz): δ = 11.66 (s, 1H), 10.20 (s, 1H), 7.50 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 1.55 (s, 9H), 1.51 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 163.6, 156.8, 153.6, 153.3, 129.8, 123.8, 114.0, 83.5, 79.4, 55.4, 28.2, 28.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₁₈H₂₈N₃O₅: 366.2023; found: 366.2033; IR: 2982, 1726, 1507, 1297, 764 cm⁻¹.

Synthesis of 1-[2,3-di(tert-butoxycarbonyl)guanidino]-naphthalene (4h)

The general procedure was followed (3.22 mmol scale). The crude residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give 4h as a colourless solid: Yield 1.06 g (85%); m.p. 146–148°C; ¹H NMR (CDCl₃, 500 MHz): δ = 11.72 (s, 1H), 10.55 (s, 1H), 8.20 (s, 1H), 7.79–7.84 (m, 3H), 7.67–7.70 (m, 1H), 7.50–7.40 (m, 2H), 1.58 (s, 9H), 1.55 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ = 163.6, 153.6, 153.4, 134.3, 133.7, 130.9, 128.5, 127.8, 127.5, 126.2, 125.1, 121.9, 119.2, 83.8, 79.7, 28.2, 28.1; HRMS (ESI) m/z [M + H]⁺ calcd for C₂₁H₂₈N₃O₄: 386.2074; found: 386.2081; IR: 2972, 1716, 1507, 1371 cm⁻¹.

General procedure for the synthesis of guanidines

Synthesis of 1-phenylguanidine trifluoroacetate (5a)

1-[2,3-Di(tert-butoxycarbonyl)guanidino]-4-benzene (4a) (0.95 g, 2.83 mmol) was dissolved in CF₃COOH (3 mL) and CHCl₃ (3 mL). The resulting mixture was stirred for 5 h at 50°C and then evaporated to dryness. The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5a as a colourless solid²¹: Yield 0.6 g (85%); m.p. 160–163°C (lit. 175–177°C); ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.25 (s, 1H), 7.73 (s, 4H), 7.45 (t, J = 7.8 Hz, 2H), 7.34–7.18 (m, 3H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.3 (q, J = 32.4 Hz), 156.4, 135.9, 130.1, 126.7, 124.7, 117.3 (q, J = 297.2 Hz); HRMS (ESI) m/z [M + H]⁺ calcd for C₇H₁₀N₃: 136.0869; found: 136.0868.

Synthesis of 1-(4-fluorophenyl)guanidine trifluoroacetate (5b)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5b as a colourless solid: Yield 0.6 g (80%); m.p. 145–148°C. ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.11 (s, 1H), 7.66 (s, 4H), 7.29 (d, J = 8.1 Hz, 4H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.9 (d, J = 241.9 Hz), 160.1 (q, J = 32.0 Hz), 156.8, 132.0, 127.9 (d, J = 8.8 Hz), 117.4 (q, J = 296.0 Hz) 116.8 (d, J = 22.6 Hz); HRMS (ESI) m/z [M + H]⁺ calcd for C₇H₉FN₃: 154.0755; found: 154.0785; IR: 3165, 1502, 1436, 1178 cm⁻¹.

Synthesis of 1-(p-tolyl)guanidine trifluoroacetate (5c)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5c as a colourless solid: Yield 0.51 g (68%); m.p. 77–80°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.11 (s, 1H), 7.63 (s, 4H), 7.13–7.26 (m, 4H), 2.32 (s, 3H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.0 (q, J = 32.4 Hz), 156.6, 136.3, 133.1, 130.5, 125.1, 117.3 (q, J = 297.3 Hz), 20.9; HRMS (ESI) m/z [M + H]⁺ calcd for C₈H₁₂N₃: 150.1026; found: 150.1028.

Synthesis of 1-(4-bromo-2-methylphenyl)guanidine trifluoroacetate (5d)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5d as a colourless solid: Yield 0.66 g (68%); m.p. 145–148°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.89 (s, 1H), 7.46–7.61 (m, 6H), 7.18 (d, J = 8.3 Hz, 1H), 2.22 (s, 3H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.2 (q, J = 32.1 Hz), 156.9, 138.5, 134.0, 133.4, 130.4, 130.2, 121.0, 117.3 (q, J = 297.1 Hz), 17.4; HRMS (ESI) m/z [M (⁷⁹Br) + H]⁺ calcd for C₈H₁₁BrN₃: 228.0131; [M (⁸¹Br) + H]⁺: 230.0110; found: 228.0135; 230.0118; IR: 3141, 1494, 1265, 1130, 719 cm⁻¹.

Synthesis of 1-(3-chlorophenyl)guanidine trifluoroacetate (5e)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5e as a colourless solid: Yield 0.52 g (65%); m.p. 134–137°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.39 (s, 1H), 7.87 (s, 4H), 7.57–7.09 (m, 4H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.4 (q, J = 32.5 Hz), 156.41, 137.7, 134.1, 131.6, 126.4, 124.5, 123.3, 117.3 (q, J = 296.9 Hz); HRMS (ESI) m/z [M (³⁵Cl) + H]⁺ calcd for C₇H₉ClN₃: 170.0480; [M (³⁷Cl) + H]⁺: 172.0450; found: 170.0487; 172.0455; IR: 3466, 3133, 1487, 1265 cm⁻¹.

Synthesis of 1-(4-chlorophenyl)guanidine trifluoroacetate (5f)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5f as a colourless solid²¹: Yield 0.7 g (87%); m.p. 124–127°C (lit. 139–141°C); ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.35 (s, 1H), 7.82 (s, 4H), 7.27–7.50 (m, 4H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.5 (q, J = 33.1 Hz), 156.5, 135.0, 130.9, 130.0, 126.7, 117.3 (q, J = 296.7 Hz); HRMS (ESI) m/z [M (³⁵Cl) + H]⁺ calcd for C₇H₉ClN₃: 170.0480; [M (³⁷Cl) + H]⁺: 172.0450; found: 170.0498; 172.0468.

Synthesis of 1-(4-methoxyphenyl)guanidine trifluoroacetate (5g)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5g as a colourless solid: Yield 0.67 g (85%); m.p. 124–127°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.87 (s, 1H), 7.50 (s, 4H), 7.00–7.19 (m, 4H), 3.77 (s, 3H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 159.9 (q, J = 31.9 Hz), 158.4, 156.9, 128.1, 127.5, 117.4 (q, J = 297.5 Hz), 115.2, 55.8; HRMS (ESI) m/z [M + H]⁺ calcd for C₈H₁₂N₃O: 166.0975; found: 166.0984; IR: 3153, 1497, 1278, 1126, 717.

Synthesis of 1-(naphthalen-2-yl)guanidine trifluoroacetate (5h)

The general procedure was followed (2.83 mmol scale). The crude residue was triturated with 50% ethyl acetate in petroleum ether (3 mL) to give 5h as a colourless solid: Yield 0.7 g (83%); m.p. 137–140°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.36 (s, 1H), 8.05–7.90 (m, 3H), 7.79 (d, J = 8.1 Hz, 5H), 7.63–7.47 (m, 2H), 7.38–7.40 (m, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 160.03 (q, J = 31.9 Hz), 156.6, 133.7, 133.4, 131.7, 129.9, 128.1, 128.0, 127.1, 126.5, 123.8, 122.6, 117.4 (q, J = 297.7 Hz); HRMS (ESI) m/z [M + H]⁺ calcd for C₁₁H₁₂N₃: 186.1026; found: 186.1038; IR: 3172, 1507, 1250, 1126, 717 cm⁻¹.

General procedure for the synthesis of N-arylpyrimidines

Synthesis of 2-(phenylamino)pyrimidine-5-carbaldehyde (6a)

1-Phenylguanidine trifluoroacetate (5a) (0.92 g, 3.7 mmol), bis(hexafluorophosphate) Arnold salt (1d) (1.75 g, 3.7 mmol) and K₂CO₃ (1.02 g, 7.4 mmol) were dissolved in methanol (20 mL) and water (7 mL). The mixture was stirred at 50°C for 6 h. The solvent was removed in vacuum and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layer was dried over Na₂SO₄, filtered and the solvent removed in vacuum. The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6a as a light yellow solid²²: Yield 0.68 g (92%); m.p. 183–184°C; ¹H NMR (CDCl₃, 500 MHz): δ = 9.90 (s, 1H), 8.88 (s, 2H), 8.06 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ = 187.5, 161.7, 160.6, 137.6, 129.1, 124.6, 122.1, 120.7; LRMS: (ESI): m/z (%): 200 (100) [M + 1]⁺.

Synthesis of 2-[(4-fluorophenyl)amino]pyrimidine-5-carbaldehyde (6b)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6b as a light yellow solid: Yield 0.70 g (87%); m.p. 213–215°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.50 (s, 1H), 9.84 (s, 1H), 8.90 (s, 2H), 7.76–7.79 (m, 2H), 7.19 (t, J = 8.7 Hz, 2H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 189.3, 161.7, 160.9, 158.6 (d, J = 240.2 Hz), 135.7, 122.7 (d, J = 7.9 Hz), 122.0, 115.7; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₉FN₃O: 218.0724; found: 218.0731; IR: 3260, 1684, 1510, 1352 cm⁻¹.

Synthesis of 2-(p-tolylamino)pyrimidine-5-carbaldehyde (6c)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6c as a light yellow solid: Yield 0.71 g (90%); m.p. 168–170°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.39 (s, 1H), 9.82 (s, 1H), 8.88 (s, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 2.27 (s, 3H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 189.2, 161.8, 160.9, 136.7, 132.8, 129.4, 121.7, 120.9, 20.9; LRMS (ESI): m/z (%): 214 (100) [M + 1]⁺.

Synthesis of 2-[(4-bromo-2-methylphenyl)amino]pyrimidine-5-carbaldehyde (6d)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6d as a pink solid: Yield 0.90 g (83%); m.p. 189–191°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 9.90 (s, 1H), 9.80 (s, 1H), 8.81 (s, 2H), 7.50 (s, 1H), 7.40 (d, J = 7.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 2.20 (s, 3H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 189.2, 162.8, 161.1, 136.7, 136.6, 133.2, 129.3, 128.7, 121.7, 118.4, 18.1; HRMS (ESI): m/z [M (⁷⁹Br) + H]⁺ calcd for C₁₂H₁₁BrN₃O: 292.0080; [M (⁸¹Br) + H]⁺: 294.0060; found: 292.0076; 294.0059; IR: 3244, 1684, 1518, 1360 cm⁻¹.

Synthesis of 2-[(3-chlorophenyl)amino]pyrimidine-5-carbaldehyde (6e)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6e as a yellow solid: Yield 0.70 g (81%); m.p. 197–200°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.60 (br, 1H), 9.86 (s, 1H), 8.95 (s, 2H), 7.98 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 189.4, 161.6, 160.8, 141.0, 133.4, 130.7, 123.1, 122.4, 119.7, 118.9; HRMS (ESI): m/z [M (³⁵Cl) + H]⁺ calcd for C₁₁H₉ClN₃O: 234.0429; [M (³⁷Cl) + H]⁺: 236.0399; found: 234.0427; 236.0396; IR: 3260, 3217, 1661, 1510, 766 cm⁻¹.

Synthesis of 2-[(4-chlorophenyl)amino]pyrimidine-5-carbaldehyde (6f)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6f as a light yellow solid: Yield 0.69 g (80%); m.p. 191–194°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.60 (s, 1H), 9.86 (s, 1H), 8.93 (s, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H); ¹³C NMR (DMSO-d₆, 125 MHz): δ = 189.4, 161.6, 160.9, 138.4, 128.9, 127.2, 122.2, 122.1; LRMS (ESI): m/z (%): 234 (100) [M (³⁵Cl) + 1]⁺, 236 (35) [M (³⁷Cl) + 1]⁺.

Synthesis of 2-[(4-methoxyphenyl)amino]pyrimidine-5-carbaldehyde (6g)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6g as a yellow solid: Yield 0.76 g (90%); m.p. 145–146°C; ¹H NMR (CDCl₃, 500 MHz): δ = 9.87 (s, 1H), 8.83 (s, 2H), 7.53 (d, J = 8.9 Hz, 2H), 7.28 (s, 1H), 6.96 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ = 187.5, 162.0, 156.9, 130.4, 123.2, 121.8, 114.3, 55.5; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₁N₃NaO₂: 252.0743; found: 252.0472; IR: 3276, 1669, 1507, 1365 cm⁻¹.

Synthesis of 2-(naphthalen-2-ylamino)pyrimidine-5-carbaldehyde (6h)

The general procedure was followed (3.7 mmol scale). The crude residue was purified by column chromatography (50% ethyl acetate in petroleum ether) to give 6h as a light yellow solid: Yield 0.81 g (88%); m.p. 186–189°C; ¹H NMR (DMSO-d₆, 500 MHz): δ = 10.71 (s, 1H), 9.88 (s, 1H), 8.98 (s, 2H), 8.44 (s, 1H), 7.42–7.89 (m, 6H); ¹³C NMR (DMSO-d₆, 150 MHz): δ = 189.3, 161.9, 160.9, 137.0, 133.8, 130.1, 128.6, 127.9, 127.7, 126.9, 125.1, 122.1, 121.5, 116.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₂N₃O: 250.0975; found: 250.0976; IR: 3267, 1669, 1516, 1374 cm⁻¹.

Supplemental Material

Supplementary_Information2020.02.14b – Supplemental material for Synthesis of 2-arylamino-5-formyl-pyrimidines from the bis(hexafluorophosphate) Arnold salt

Supplemental material, Supplementary_Information2020.02.14b for Synthesis of 2-arylamino-5-formyl-pyrimidines from the bis(hexafluorophosphate) Arnold salt by Qiuyu Lu, Wei He, Wen Sun, Ye Feng, Li Zhan and Yu Luo in Journal of Chemical Research

Footnotes

Acknowledgements

The authors thank the Laboratory of Organic Functional Molecules and the Sino-French Institute of ECNU for their support.

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) received no financial support for the research, authorship and/or publication of this article.

ORCID iD

Yu Luo

Supplemental material

Supplemental material for this article is available online.

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