Sonogashira coupling reactions: Synthesis of 4-substituted-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd

Abstract

An efficient method is developed for the synthesis of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines via palladium-catalyzed Sonogashira reactions of 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine with electron-poor aryl iodides in acetonitrile at room temperature. Excellent yields of the products were obtained in reaction times of 9–11 h.

Keywords

aryl iodides CuI Pd propargyl bromide pyrimidines Sonogashira reaction

Introduction

Heterocycles bearing a pyrimidine moiety are reported to show a broad spectrum of pharmacological properties such as antibacterial,¹ anti-HIV,² and anticancer.³ In this regard, antitumor and antiviral are two of the most extensively reported activities of pyrimidine analogs.⁴ Moreover, they possess insecticidal and herbicidal activities.^5–8

Transition-metal-mediated cross-coupling reactions have proven to be powerful tools for mild and highly efficient carbon–carbon bond formation.^9–11 Palladium (Pd)-catalyzed cross-coupling reactions are among the most versatile processes for carbon–carbon bond formation. Among these reactions, the coupling reactions of terminal alkynes with aryl and vinyl halides (Sonogashira reactions) play important roles in modern synthetic chemistry.^12,13 This reaction is one of the most widely used C–C bond-forming reactions,^14,15 furnishing an impressive route to aryl alkynes, which are interesting intermediates for the preparation of a variety of natural products,^16–19 pharmaceuticals,²⁰ and organic materials.^21,22

Accordingly, and based on our progressive endeavors in developing Pd-catalyzed reactions of acetylenes leading to heterocyclic compounds of biological significance via environmentally benign synthetic methodologies,^23–27 herein we report the synthesis of new derivatives of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidine via the Pd-catalyzed Sonogashira coupling reactions of 4-methyl-2-(methylthio)-6-(prop-2-ynyloxy)pyrimidine with aryl iodides.

Results and discussion

Treatment of 6-methyl-2-(methylthio)pyrimidine-4(3H)-one (1) with propargyl bromide (2) in dimethylformamide (DMF) in the presence of K₂CO₃ at room temperature led to 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) and N¹- or N³-propynylated pyrimidine (4) (Scheme 1).

Scheme 1.

Alkylation of pyrimidine (1) at the O- and N¹- or N³-positions with propargyl bromide.

Structures (3) and (4) were established by comparing their infrared (IR) spectra. The Fourier-transform infrared (FTIR) spectra of compound (1), O-propynylated pyrimidine (3), and N¹- or N³-propynylated pyrimidine (4) are shown in Figure 1. In the IR spectrum of compound (1), a sharp N–H stretching vibration band was observed at 3253 cm⁻¹. Moreover, the band at 1698 cm⁻¹ was assigned to the C=O stretching of the carbonyl group (Figure 1(a)). The IR spectra for compound (4) showed an adsorption band at 1645 cm⁻¹, which was assigned to the C=O stretching of the carbonyl group (Figure 1(c)). In comparison, in the FTIR spectrum of O-propynylated pyrimidine (3), the characteristic band for the C=O group was not present (Figure 1(b)). Furthermore, the IR spectra for compounds (3) and (4) showed new bands at 3167 and 3124 cm⁻¹, respectively, which were assigned to the C–H stretching of the acetylene group.

Figure 1.

FTIR spectra for (a) compound (1), (b) O-propynylated pyrimidine (3), and (c) N¹- or N³-propynylated pyrimidine (4).

The ¹H NMR spectrum for compound (3) showed a singlet for the SCH₃ protons at δ 2.38, a triplet at δ 2.51 for CH, a singlet for the CH₃ protons at δ 2.56, a doublet for the CH₂ protons at δ 5.00, and a singlet at δ 6.30 for the CH of the pyrimidine ring.

For optimization of the reaction conditions, we chose the reaction of compound (3) with 1-iodo-4-nitrobenzene (5a) in the presence of PdCl₂(PPh₃)₂ (5 mol%) and CuI (10 mol%) as the model reaction, and the effects of the solvent, base, and various catalysts were examined. The results obtained are shown in Table 1.

Table 1.

Effects of various solvents, catalysts, bases, and temperatures on the reaction of compound (3) with 1-iodo-4-nitrobenzene (5a).^a

Entry	Catalyst (mol%)	Solvent	Base	Temperature (°C)	Time (h)	Yield (%)^b
1	PdCl₂(PPh₃)₂ (5)	DMF	Et₃N	r.t.	9	30
2	PdCl₂(PPh₃)₂ (5)	1,4-Dioxane	Et₃N	r.t.	9	40
3	PdCl₂(PPh₃)₂ (5)	EtOH	Et₃N	r.t.	9	10
4	PdCl₂(PPh₃)₂ (5)	CH₃CN	Et₃N	r.t.	6	95
5	PdCl₂(PPh₃)₂ (5)	CH₃CN	DIPEA	r.t.	9	80
6	PdCl₂(PPh₃)₂ (5)	CH₃CN	Pyrrolidine	r.t.	9	80
7	PdCl₂(PPh₃)₂ (5)	CH₃CN	Pyridine	r.t.	9	70
8	PdCl₂(PPh₃)₂ (5)	CH₃CN	Piperidine	r.t.	9	84
9	PdCl₂(PhCN)₂ (5)	CH₃CN	Et₃N	r.t.	9	80
10	Pd/C (5)	CH₃CN	Et₃N	r.t.	9	70
11	PdCl₂(PPh₃)₂ (2)	CH₃CN	Et₃N	r.t.	7	76
12	PdCl₂(PPh₃)₂ (10)	CH₃CN	Et₃N	r.t.	6	95
13	CuI (10)	CH₃CN	Et₃N	r.t.	20	−
14	PdCl₂(PPh₃)₂ (5)	CH₃CN	Et₃N	50	9	94
15	PdCl₂(PPh₃)₂ (5)	CH₃CN	Et₃N	80	9	95

DMF: dimethylformamide; r.t.: room temperature; DIPEA: diisopropylethylamine.

Reaction conditions: compound (3) (1.2 mmol), 1-iodo-4-nitrobenzene (5a) (1.0 mmol), CuI (twice the amount relative to the palladium catalyst), base (2.0 mmol), solvent (3 mL).

Isolated yield.

The reactions were performed using different solvents such as DMF, CH₃CN, EtOH, and 1,4-dioxane in the presence of Et₃N as the base at room temperature. As can be seen, the highest reaction yield was obtained when CH₃CN was used as the solvent (Table 1, entry 4). Moreover, other parameters such as the base and reaction temperature were also investigated. When organic bases such as Et₃N, diisopropylethylamine, pyrrolidine, pyridine, and piperidine were used (Table 1, entries 4–8), the best results were obtained in the case of Et₃N (Table 1, entry 4). Also, several catalytic palladium sources such as Pd/C, Pd(PhCN)₂Cl₂, and PdCl₂(PPh₃)₂ were screened in CH₃CN. It was found that PdCl₂(PPh₃)₂ was the best catalyst for this reaction condition (Table 1, entry 4). The conditions with respect to the amount of catalyst were optimized. Decreasing the loading of the catalyst to 2.0 mol% lowered the reaction yield dramatically (Table 1, entry 11). However, increasing the amount of catalyst to 10 mol% only shortened the reaction time and did not have any effect on the reaction yield (Table 2, entry 12). No Sonogashira coupling reaction was observed when CuI alone was used as the catalyst (Table 1, entry 13). Furthermore, the effect of the temperature on the reaction yield was investigated. As shown in Table 1, increasing the temperature did not improve the reaction yield (Table 2, entries 14 and 15).

Table 2.

Synthesis of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines (6a–g).^a


Entry	ArI	Product	Time (h)	m.p. (°C)	Yield (%)^b
1		6a	9	92–94	95
2		6b	9	69–71	96
3		6c	9	78–80	96
4		6d	9	96–98	97
5		6e	11	85–87	90
6		6f	11	88–90	90
7		6g	11	74–76	90

Reaction conditions: compound (3) (1.2 mmol), aryl iodide (5) (1.0 mmol), PdCl₂(PPh₃)₂ (5.0 mol%), CuI (10 mol%), CH₃CN (3 mL), Et₃N (2.0 mmol), room temperature.

Isolated yield.

Using the optimized reaction conditions (Table 1, entry 4), the scope of the reaction was explored with various electron-poor aryl iodides (5a–g) and 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) (Table 2). As can be seen, the presence of electron-withdrawing groups such as –NO₂ and –Cl on the aryl iodides was essential for a successful reaction. When phenyl iodide, p-iodoanisole, or p-iodoaniline were used as the aryl iodide, the Sonogashira coupling reaction did not occur. Besides, when less reactive aryl bromides such as 2-bromonitrobenzene, 3-bromonitrobenzene, and 4-bromonitrobenzene were used, the coupling product was not formed.

Mechanistic details for the formation of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines (6a–g) are as follows (Scheme 2): (1) formation of ArPdI (B) through oxidative addition of Pd(0) (A) to ArI;¹² (2) transmetallation of ArPdI (B) with the Cu salt of (C), generating the alkynyl palladium species (D); and (3) extrusion of Pd(0) resulting in the formation of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines (6a–g).

Scheme 2.

A plausible mechanism for formation of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines (6a–g).

Conclusion

We have described an efficient method for the synthesis of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd–Cu through Sonogashira coupling reactions of 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) with electron-poor aryl iodides in high-to-excellent reaction yields.

Experiment

General

The reagents and solvents used were supplied from Merck, Fluka, or Aldrich. Melting points were determined using a brand electro-thermal C14500 apparatus. The reaction progress and the purity of compounds were monitored using thin-layer chromatography (TLC) using silica gel plates (Merck 60 F250). All known compounds were identified by comparing their melting points and ¹H NMR data with those of authentic samples. The ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on a Bruker Avance DPX-250 FT-NMR spectrometer. The chemical shifts are given as δ values against tetramethylsilane as the internal standard, and the J values are given in Hertz. Microanalysis was performed on a PerkinElmer 240-B microanalyzer.

Synthesis of 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) and N¹- or N³-propynylated pyrimidine (4)

Propargyl bromide (2) (1.2 mmol, 0.10 mL) was added slowly to a stirred mixture of 6-methyl-2-(methylthio)pyrimidine-4(3H)-one (1) (1.0 mmol, 0.15 g) and K₂CO₃ (2.0 mmol, 0.27 g) in dry DMF (4 mL) at room temperature, and the mixture was stirred at room temperature for 10 h. Upon completion of the reaction, the solvent was evaporated under vacuum, and the resulting residue was washed with water. The residue was finally purified by flash column chromatography (hexane/ethyl acetate = 10:1) to give the titles compounds.

Compound (3): TLC (hexane/ethyl acetate = 10:1) R_f = 0.7; yield 70%; white powder; m.p. 80–82 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.38 (s, 3H, CH₃), 2.51 (t, J = 2.4 Hz, 1H, CH), 2.56 (s, 3H, CH₃), 5.00 (d, J = 2.4 Hz, 2H, CH₂), 6.30 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 53.6, 74.9, 78.1, 102.0, 167.9, 168.1, 171.3; IR (KBr): 3167, 2925, 2116, 1581, 1404, 1339, 1041 cm⁻¹. Anal. calcd for C₉H₁₀N₂OS: C, 55.65; H, 5.19; N, 14.42; found: C, 55.82; H, 5.28; N, 14.58%.

Compound (4): TLC (hexane/ethyl acetate = 10:1) R_f = 0.52; yield 30%; white powder; m.p. 122–124 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.15 (s, 3H, CH₃), 2.20 (t, J = 2.4 Hz, 1H, CH), 2.53 (s, 3H, CH₃), 4.76 (d, J = 2.4 Hz, 2H, CH₂), 6.00 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 15.1, 23.8, 32.6, 72.3, 107.6, 161.1, 161.3, 162.7; IR (KBr): 3124, 3001, 1645, 1581, 1543, 1461 cm⁻¹. Anal. calcd for C₉H₁₀N₂OS: C, 55.65; H, 5.19; N, 14.42; found: C, 55.79; H, 5.11; N, 14.28%.

Synthesis of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines (6a–g)

A mixture of aryl iodide (5) (1.0 mmol), PdCl₂(PPh₃)₂ (5.0 mol%), CuI (10 mol%), and Et₃N (2 mmol, 0.3 mL) was stirred in CH₃CN (3 mL) at room temperature for 20 min under an argon atmosphere. 4-Methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) (1.0 mmol, 0.19 g), was then added and the mixture was stirred at room temperature. After completion of the reaction, the crude product was subjected to flash column chromatography (hexane/ethyl acetate = 10:1) to afford the pure product (see Table 2).

4-Methyl-2-(methylthio)-6-{[3-(4-nitrophenyl)prop-2-yn-1-yl]oxy}pyrimidine (6a): Yield 95%; white powder; m.p. 92–94 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.43 (s, 3H, CH₃), 2.60 (s, 3H, CH₃), 5.28 (s, 2H, CH₂), 6.36 (s, 1H, ArH), 7.62 (d, J = 9 Hz, 2H, ArH), 8.21–8.23 (m, 2H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 54.1, 84.6, 88.9, 102.0, 123.6, 129.0, 132.6, 147.4, 167.9, 168.3, 171.4. Anal. calcd for C₁₅H₁₃N₃O₃S: C, 57.13; H, 4.16; N, 13.33; found: C, 57.32; H, 4.25; N, 13.49%.

4-Methyl-2-(methylthio)-6-{[3-(2-nitrophenyl)prop-2-yn-1-yl]oxy}pyrimidine (6b): Yield 96%; white powder; m.p. 69–71 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.41 (s, 3H, CH₃), 2.59 (s, 3H, CH₃), 5.30 (s, 2H, CH₂), 6.36 (s, 1H, ArH), 7.47–7.53 (m, 2H, ArH), 7.57–7.67 (m, 2H, ArH), 8.05–8.08 (m, 2H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 54.4, 81.7, 91.5, 102.0, 117.6, 124.6, 129.1, 132.8, 135.0, 149.0, 168.0, 168.2, 171.4. Anal. calcd for C₁₅H₁₃N₃O₃S: C, 57.13; H, 4.16; N, 13.33; found: C, 57.34; H, 4.27; N, 13.15%.

4-Methyl-2-(methylthio)-6-{[3-(3-nitrophenyl)prop-2-yn-1-yl]oxy}pyrimidine (6c): Yield 96%; white powder; m.p. 78–80 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.42 (s, 3H, CH₃), 2.60 (s, 3H, CH₃), 5.26 (s, 2H, CH₂), 6.35 (s, 1H, ArH), 7.53 (t, J = 7.8 Hz, 1H, ArH), 7.76 (d, J = 7.5 Hz, 1H, ArH), 8.22–8.19 (m, 1H, ArH), 8.31 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 29.7, 54.1, 84.1, 86.3, 102.0, 123.4, 124.0, 126.6, 129.4, 137.4, 148.8, 167.9, 168.3, 171.4. Anal. calcd for C₁₅H₁₃N₃O₃S: C, 57.13; H, 4.16; N, 13.33; found: C, 57.31; H, 4.23; N, 13.45%.

4-{[3-(4-Chloro-3-nitrophenyl)prop-2-yn-1-yl]oxy}-6-methyl-2-(methylthio)pyrimidine (6d): Yield 97%; white powder; m.p. 96–98 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.42 (s, 3H, CH₃), 2.60 (s, 3H, CH₃), 5.24 (s, 2H, CH₂), 6.35 (s, 1H, ArH), 7.51–7.59 (m, 2H, ArH), 7.96 (d, J = 3 Hz, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 54.0, 83.1, 87.3, 102.0, 122.4, 127.2, 128.5, 131.9, 135.8, 167.8, 168.3, 171.4. Anal. calcd for C₁₅H₁₂ClN₃O₃S: C, 51.51; H, 3.46; N, 12.01; found: C, 51.71; H, 3.55; N, 12.19%.

4-{[3-(2-Chloro-4-nitrophenyl)prop-2-yn-1-yl]oxy}-6-methyl-2-(methylthio)pyrimidine (6e): Yield 90%; white powder; m.p. 85–87 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.41 (s, 3H, CH₃), 2.59 (s, 3H, CH₃), 5.29 (s, 2H, CH₂), 6.35 (s, 1H, ArH), 8.58–8.58 (m, 2H, ArH), 8.07 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 54.2, 80.7, 92.7, 102.0, 116.1, 124.9, 133.1, 135.1, 135.8, 150.1, 167.9, 168.3, 171.4. Anal. calcd for C₁₅H₁₂ClN₃O₃S: C, 51.51; H, 3.46; N, 12.01; found: C, 51.69; H, 3.56; N, 12.21%.

4-{[3-(4-Chloro-2-nitrophenyl)prop-2-yn-1-yl]oxy}-6-methyl-2-(methylthio)pyrimidine (6f): Yield 90%; white powder; m.p. 88–90 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.43 (s, 3H, CH₃), 2.61 (s, 3H, CH₃), 5.33 (s, 2H, CH₂), 6.37 (s, 1H, ArH), 7.66 (d, J = 8.7 Hz, 1H, ArH), 8.09–8.13 (m, 1H, ArH), 8.31 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 23.8, 54.1, 81.7, 94.2, 102.0, 121.4, 124.5, 128.8, 134.0, 137.2, 167.8, 168.4, 171.4 ppm. Anal. calcd for C₁₅H₁₂ClN₃O₃S: C, 51.51; H, 3.46; N, 12.01; found: C, 51.32; H, 3.37; N, 12.17%.

4-{[3-(2-Methyl-4-nitrophenyl)prop-2-yn-1-yl]oxy}-6-methyl-2-(methylthio)pyrimidine (6g): Yield 90%; white powder; m.p. 74–76 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.43 (s, 3H, CH₃), 2.52 (s, 3H, CH₃), 2.60 (s, 3H, CH₃), 5.31 (s, 2H, CH₂), 6.36 (s, 1H, ArH), 7.56 (d, J = 8.7 Hz, 1H, ArH), 8.01–8.04 (m, 1H, ArH), 8.10 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ 14.0, 20.7, 23.8, 54.2, 83.7, 92.5, 102.0, 120.7, 124.2, 128.8, 132.8, 142.2, 147.3, 167.9, 168.3, 171.4. Anal. calcd for C₁₆H₁₅N₃O₃S: C, 58.34; H, 4.59; N, 12.76; found: C, 58.53; H, 4.67; N, 12.59%.

Supplemental Material

supplementary_information – Supplemental material for Sonogashira coupling reactions: Synthesis of 4-substituted-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd–Cu

Supplemental material, supplementary_information for Sonogashira coupling reactions: Synthesis of 4-substituted-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd–Cu by Fatemeh Rezaeimanesh, Mohammad Bakherad and Hossein Nasr-Isfahani in Journal of Chemical Research

Footnotes

Acknowledgements

The authors gratefully acknowledge the support of the Research Council of the Shahrood University of Technology.

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 study was financially supported by the Research Council of the Shahrood University of Technology.

ORCID iD

Mohammad Bakherad

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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Sonogashira coupling reactions: Synthesis of 4-substituted-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd–Cu

Abstract

Keywords

Introduction

Results and discussion

Conclusion

Experiment

General

Synthesis of 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) and N1- or N3-propynylated pyrimidine (4)

Synthesis of 4-(3-arylprop-2-ynyloxy)-6-methyl-2-(methylthio)pyrimidines (6a–g)

Supplemental Material

supplementary_information – Supplemental material for Sonogashira coupling reactions: Synthesis of 4-substituted-6-methyl-2-(methylthio)pyrimidines catalyzed by Pd–Cu

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material

Synthesis of 4-methyl-2-(methylthio)-6-(prop-2-yn-1-yloxy)pyrimidine (3) and N¹- or N³-propynylated pyrimidine (4)