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. 2022 May 24;7(22):18930–18939. doi: 10.1021/acsomega.2c01925

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines

Mateus Mittersteiner †,‡, Genilson S Pereira †, Ludger A Wessjohann ‡, Helio G Bonacorso †, Marcos A P Martins †, Nilo Zanatta †,*
PMCID: PMC9178747  PMID: 35694463

Abstract

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This study reports two strategies for preparing O-alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1H)-ones: a linear protocol of alkylation, using a CCC-building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective O-alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70–98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.

Introduction

Pyrimidines have been used as suitable starting materials for the synthesis of novel scaffolds that are parent to DNA bases and derivatives, thus targeting compounds with relevant biological and pharmacological properties.1−5 For example, trihalomethyl-substituted pyrimidines have been used as caspase inhibitors,6 hepatitis C inhibitors,7,8 antiplasmodials,9 NTPDase inhibitors,10 as well as anticancer agents.11 Additionally, molecules that contain more than one pyrimidine core have been reported to act as antibacterial and antifungal agents.12,13

There have been several studies regarding the chemoselectivity between N- and O-alkylation14−19 (or S-alkylation in pyrimidine-2(1H)-thiones20−22) when preparing alkyl/aryl derivatives; however, directing the reaction toward furnishing one sole product in the absence of protecting groups or specific catalysts is a problem yet to overcome.23 More specifically, several derivatization techniques have already been reported for the synthesis of trifluoromethyl-containing pyrimidines;24−28 however, the most widely explored one is still alkylation using alkyl halides or esters,29 and others are based on the application of TMS-protected pyrimidines,29 cyclocondensation strategies using starting materials that allow the desired substitution pattern,30−32 and copper-mediated coupling reactions with aryl boronic acids.33

The direct alkylation of the 4-(trifluoromethyl)pyrimidin-2(1H)-ones with alkyl or allyl halides furnishes a mixture of N- and O-alkylated products in ratios that depend mostly on the substrate choice.18,23,34 When the same reaction was performed with a more complex alkylating agent (5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, a brominated enone), only the N-alkylated pyrimidine was observed.35 The use of derivatives of this brominated enone as resourceful and selective alkylating agents for several other complex nucleophiles (e.g., vinylic amines,36 pyrazoles, and others37) has already been explored. Thus, inspired by the selectivity observed previously in obtaining N-alkylated derivatives,35 this present work started to study the reactivity of its counterpart, the O-alkylated pyrimidines (3) containing a β-enaminone moiety, in a [3 + 3] cyclocondensation reaction with 2-methylisothiourea sulfate (Scheme 1, route 1), and the selectivity of 4-(halomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines 6 as O-alkylating agents of 4-(trifluoromethyl)pyrimidin-2(1H)-ones 1 (Scheme 1, route 2).

Scheme 1. Linear (through Cyclocondensation) and Convergent (through Alkylation) Strategies Adopted for the Work Presented Herein.

Scheme 1

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Results and Discussion

Initially, a series of 4-alkoxyvinyl trifluoromethyl ketones was prepared through the acylation reaction of enol ethers (readily available or generated in situ from the corresponding dimethyl acetals) with trifluoroacetic anhydride, in the presence of pyridine. These were reacted with urea in the presence of HCl to furnish a series of 6-substituted-4-(trifluoromethyl)pyrimidin-2(1H)-ones 1a–m.38 The brominated enaminone 2 and enones 5a–b were synthesized in accordance with previously reported procedures.39,40

Because two reaction pathways are possible for obtaining the desired pyrimidine compounds 4 (Scheme 1), we decided to evaluate which one is more feasible in terms of isolated yield and purification of the final compound. Route 1 uses a linear strategy involving the selective O-alkylation of pyrimidin-2(1H)-one 1a, using brominated enaminones to furnish 3 in 92% yield.41 The cyclocondensation of the latter 3 using 2-methyl-2-thiopseudourea sulfate furnishes 4a in low yields (8–10%)—see Scheme 2. Longer reaction times (up to 48 h) and higher amounts of the NCN-dinucleophile were used in attempts to improve the yield; however, in all the tests done, pyrimidine 3 was always recovered in large amounts.

Scheme 2. Linear Strategy to Selectively Prepare the O-Alkyl Pyrimidine 4a.

Scheme 2

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The lower yield obtained for pyrimidine 4a when prepared from enaminone 2 can be attributed to the lower reactivity of the β-position when an amino group is present. When comparing to a less hindered and more labile alkoxy group (methoxy or ethoxy, usually used for these reactions) combined with a less reactive dinucleophile such as 2-methyl-2-thiopseudourea sulfate, this resulted in a significant decrease in the isolated yield of 4a.24 With the aim of using a methoxy group at the β-position, the alkylation of pyrimidin-2(1H)-one 1a with brominated enone 5a was performed. However, in the 1H NMR analysis, only a mixture of starting materials along with peaks that could not be assigned to any plausible structure was obtained. Given these results, an alternative convergent strategy was envisioned.

In this second strategy, the initial cyclocondensation takes place earlier. Brominated enone 5a and thiopseudourea sulfate in hydrochloric acid solution furnish 4-(chloromethyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (6a) in 65% yield (Scheme 3).42 The alkylating pyrimidine-containing agent was then reacted with pyrimidin-2(1H)-one 1a to selectively furnish the O-alkylated product, without any traces of the N-alkylated derivative (confirmed by the 1H NMR analysis of the crude reaction, after isolation with CH2Cl2).

Scheme 3. Convergent Strategy to Selectively Prepare O-Alkylated Pyrimidine 4a and 1H-13C HMBC Correlations Used for the Assignment of the Isomer and Structural Elucidation.

Scheme 3

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Despite the fact that the strategy was successful, the isolated yield of the reaction was still moderate to low using MeCN as the solvent, K2CO3 as the base at r.t. (23% yield), and reflux (53% yield) for 16 h, that is, conditions adapted from the literature.41 This could be caused by the poor nature of chloride as the leaving group used in the nucleophilic substitution reaction. In order to verify this before optimizing the reaction conditions, the corresponding 4-(bromo/iodomethyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidines 6b and 6c were prepared in accordance with the literature.43 The alkylation reactions were performed using pyrimidin-2(1H)-one 1a and K2CO3 in refluxing MeCN for 16 h. By using brominated (6b) and iodinated (6c) derivatives, yields of 80 and 87% were observed, respectively. It is worth highlighting that the nature of the leaving group did not affect the selectivity of the reaction, and O-alkylated pyrimidine 4a was obtained as the sole product in all cases.

For further optimization of the reaction conditions, we considered 6-phenyl-4-(trifluoromethyl)pyrimidin-2(1H)-one 1a and 4-(iodomethyl)pyrimidine 6c because the iodomethyl moiety provided the best isolated yield of 4a when comparing chloro/bromomethyl moieties. The reaction was initially done using MeCN for 16 h; however, a decrease in the yield was observed when lowering the temperature to 25 °C (76%, entry 2). After noticing that the yield improved upon heating, the disappearance of both pyrimidin-2(1H)-one 1a and pyrimidine 6c was monitored via thin layer chromatography (TLC). After 1 h in refluxing MeCN, no more starting material was detected, and product 4a could be isolated in 90% yield (entry 3). For comparison purposes, the same reaction conducted at r.t. furnished 4a in 63% (entry 4). When the solvent was changed to Me2CO, at r.t. and in refluxing conditions, yields of 70 and 90% were observed, respectively. Given the identical results for MeCN and Me2CO, we decided to perform further tests using only Me2CO, which is a much cheaper and easier-to-handle solvent. Initially, the reaction was extended to 2 h. However, no significant improvement was observed (only 1%—see entry 7). The reaction was then conducted for 0.5 and 0.25 h, which gave yields of 89 and 51%, respectively (entries 8 and 9). This indicates that refluxing acetone for 0.5 h furnishes 4a in nearly the same yield as for longer reaction times (e.g., 90–91% for 1–2 h in acetonitrile), that is, acetone provides the better option with respect to time, energy, and solvent cost.

Having defined the best reaction conditions (entry 8 in Table 1), the reaction scope was evaluated by varying the substitution patterns in starting pyrimidin-2(1H)-ones 1 and the trihalomethyl moiety (trifluoro- and trichloromethyl) in pyrimidines 6. Several aryl groups bearing electron-donating and -withdrawing groups at the 6-position of pyrimidin-2(1H)-ones 1 were used to verify their influence or limitations on the O-alkylation reaction (Table 2). As it turns out, the reactivity of neither electron-rich (4-Me, 2/3/4-OMe) nor strongly deactivated (4-Cl/Br, 4-NO2) pyrimidin-2(1H)-ones had any effect on the reactivity of the O-alkylation reaction, with 4a–j being furnished in 86–98% yields (Table 2). Functionalized compounds with 2-thienyl and 2-furyl moieties were also prepared, which furnished the tri-heterocyclic compounds 4k and 4l in 90 and 86%, respectively. When 6-methyl-4-(trifluoromethyl)pyrimidin-2(1H)-one 1m was used, the replacement of aryl groups with a methyl one resulted in a decreased isolated yield (70%). The replacement of the trihalomethyl moiety in the 4-(iodomethyl)pyrimidines 6 furnished compounds 4p–4r in high yields (91–98%).

Table 1. Optimization of Reaction Conditions for the Synthesis of O-Alkylated Pyrimidine 4aa.

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entry solvent time (h) temp. (°C) yield (%)b
1 MeCN 16.0 reflux 87
2 MeCN 16.0 25 76
3 MeCN 1.0 reflux 90
4 MeCN 1.0 25 63
5 Me2CO 1.0 25 70
6 Me2CO 1.0 reflux 90
7 Me2CO 2.0 reflux 91
8 Me2CO 0.5 reflux 89
9 Me2CO 0.25 reflux 51
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a

Reaction conditions: pyrimidin-2(1H)-one 1a (0.5 mmol, 120 mg), K2CO3 (0.5 mmol, 69 mg), pyrimidine 6c (0.5 mmol, 167 mg), solvent (5 mL).

b

Isolated yield after recrystallization from hexane/MeOH (9:1).

Table 2. Reaction Scope for the Synthesis of O-Alkylated Pyrimidines 4a–r.

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entry R X yield (%)a compound
1 C6H5 F 89 4a
2 4-Me-C6H4 F 88 4b
3 2-OMe-C6H4 F 89 4c
4 3-OMe-C6H4 F 98 4d
5 4-OMe-C6H4 F 92 4e
6 4-F-C6H4 F 90 4f
7 4-Cl-C6H4 F 86 4g
8 4-Br-C6H4 F 95 4h
9 4-NO2-C6H4 F 87 4i
10 2-naphtalenyl F 94 4j
11 2-thienyl F 90 4k
12 2-furyl F 86 4l
13 Me F 70 4m
15 i-Bu F 72 4n
17 t-Bu F 94 4o
18 C6H5 Cl 91 4p
19 4-Cl-C6H4 Cl 98 4q
20 4-Br-C6H4 Cl 98 4r
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a

Isolated yield after recrystallization from hexane/MeOH (9:1) for compounds 4a–4l, 4p–4r, and after column chromatography (hexane/AcOEt 95:5) for compounds 4m–4o. Reaction conditions: pyrimidin-2(1H)-one 1a–m (3 mmol), K2CO3 (3 mmol, 0.414 g), 4-(iodomethyl)pyrimidine 6c, 6d (3 mmol), Me2CO (15 mL), reflux, 30 min.

The methyl and isobutyl groups at the 6-position furnished the compounds in lower yields (70 and 72%—entries 13 and 14, respectively, in Table 2), which suggests that a competition reaction between N- and O-alkylation might occur. However, an analysis of the crude 1H NMR spectra only showed peaks that are attributable to the O-alkylated products and other peaks that could not be attributed to any other similar product, that is, not to N-alkylated derivatives. Despite this, previous work in the literature show that the selectivity of the alkylation reaction is harmed when 6-alkyl-4-(trifluoro/chloromethyl)pyrimidin-2(1H)-ones are used.18,23

In this present work, the isolated yield of the O-alkylated compound is comparable to the ratio previously obtained in the literature for parent reactions; however, the N-alkylated derivative of 4m was not detected, which suggests that the N-alkyl derivative of 4m is unstable and decomposes immediately after formation. Intrigued by this, we performed experiments to verify the influence of using compounds known to favor N-alkylation; that is, without any substituent at the 6-position of the pyrimidin-2(1H)-one ring.35 For this, pyrimidin-2(1H)-ones 1n–o were reacted with 4-(iodomethyl)pyrimidines 6c–d under the standard conditions (Scheme 4a). Again, no formation of either N-alkylated or O-alkylated product was detected. This suggests that the selectivity was as assumed completely toward N-alkylation, and the formed product likely was decomposed rapidly (Scheme 4).

Scheme 4. Attempts To Obtain the N-Alkylated Analogues.

Scheme 4

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(a) Alkylation of (5-methyl)-4-(trifluoromethyl)pyrimidin-2(1H)-ones 1n–1o, using 4-(iodomethyl)pyrimidines 6c and 6d and (b) Cyclocondensation of the moiety of N-alkyl pyrimidinones 7 with 2-methylisothiourea sulfate.

Because the O-alkylated pyrimidine 3 (see Scheme 2) was cyclocondensed with 2-methylisothiourea sulfate to furnish the product in low yields (8–10%), it was also tested for N-alkylated 7 (Scheme 4b). Several reaction conditions were tested in accordance with methods in the literature.44 However, again, no formation of the product was observed via either ESI-MS or 1H NMR. An attempt was also made to use TMS-protected pyrimidin-2(1H)-one 1n because this is a standard protocol when performing selective N-alkylation using esters29,45 and has been used for alkyl chlorides;46 however, only the deprotected pyrimidin-2(1H)-one 1n was isolated.

The chemoselectivity of the reaction was confirmed with the assistance of 1H-13C HSQC and HMBC experiments. Appropriate single crystals of compounds 4c and 4f were obtained through the slow evaporation of CHCl3 solutions, and single crystal X-ray analyses were performed. The ORTEP projections for compounds 4c and 4f are shown in Figure 1 and confirms the O-alkylated derivatives obtained.

Figure 1.

Figure 1

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ORTEP of compounds 4c (CCDC: 2117379) and 4f (CCDC: 2035557)—thermal ellipsoids are drawn at the 50% probability level.

The last part of our study involved the oxidation of the methylsulfanyl (-SMe) moiety. Oxone was initially chosen because of it being commonly used for this type of reaction;47−51 it was used in different solvent mixtures (e.g., MeOH/H2O, CH2Cl2/H2O, and MeCN/H2O) at either r.t. or refluxing conditions. However, no formation of the oxidized product was observed. Taking this into account, we next attempted to use m-CPBA, which is another popular oxidizing agent for such reactions.52−54 The conditions were adapted from previous parent substrates,43,55 and after 16 h (using CHCl3 at r. t.), sulfone 7 was obtained in 92% yield (Scheme 5).

Scheme 5. Oxidation of the Methylsulfanyl (-SMe) Moiety to Methylsulfonyl (-SO2Me) Using m-CPBA.

Scheme 5

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Conclusions

In summary, a fast, high-yielding, and selective protocol for the O-alkylation of pyrimidin-2(1H)-ones, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines as heterocyclic alkylating agents, was developed. None of the different conditions tested herein (halide, reaction time, solvent, or substituents) affected the chemoselectivity of the reaction, and the convergent pathway proposed herein provided a significant improvement (30 min reaction time, 70–98% yield) over the commonly adopted linear pathway through [3 + 3] cyclocondensation (48 h, 8–10% yield). The oxidation of the methylsulfanyl moiety furnished a suitable leaving group that is able to react with other nucleophiles, allowing further functionalization.

Experimental Section

Reagents were purchased and used without further purification. The procedure for obtaining the pyrimidin-2(1H)-ones 1,38 5-bromo enaminones 2,39 and 5-bromo enones 5 was described elsewhere.40 4-(Halomethyl)pyrimidines 6 were synthesized according to a reported procedure.42 TLC was performed using silica gel plates F-254, 0.25 mm thickness. For visualization, TLC plates were either placed under ultraviolet light or stained with sulfuric vanillin followed by heating. Most reactions were monitored by TLC for the disappearance of the starting material. NMR spectra were performed in CDCl3 solutions using TMS as the internal standard. 1H NMR spectra were recorded at 600 or at 400 MHz and chemical shifts δ are quoted in parts per million (ppm), and coupling constants (J) are given in hertz (Hz). 13C NMR spectra were recorded at 150 MHz or at 100 MHz. 19F NMR spectra were recorded at 564 or 376 MHz, using fluorobenzene as the external reference with the chemical shifts reported according to the CFCl3 standard. The low-resolution mass spectra were recorded on a GC–MS using EI mode (70 eV), and high-resolution mass spectroscopy (HRMS) spectra were recorded on an ESI-TOF mass spectrometer. All melting points were determined on a melting point apparatus and are uncorrected. Single crystal X-ray diffraction were recorded in a diffractometer equipped with a four circles KAPPA goniometer, PHOTON 100 CMOS array detector, graphite monochromator, and Mo-Kα (λ = 0.71073 Å) or Cu Kα radiation (λ = 1.54080 Å) radiation source. Absorption correction was performed using multiscan methods. The structure was solved and refined with an Olex2 program56 (version 1.3), by means of olex2.solve57 and olex2.refine,57 respectively. Anisotropic displacement parameters for nonhydrogen atoms were applied.

General Experimental Procedure for the Synthesis of 4a–r

To a round-bottom flask loaded with 6-substituted pyrimidin-2(1H)-ones 1a–o (3 mmol) and K2CO3 (3 mmol, 0.414 g), Me2CO (10 mL) was added. Upon stirring, a solution of 4-(iodomethyl)pyrimidines 6c–d (3 mmol) dissolved in Me2CO (5 mL) was added. The mixture was heated to reflux and stirred for 30 min. After this period, the solvent was removed under vacuum, and the residue was dissolved in CH2Cl2 (20 mL) and washed with distilled water (2× 15 mL). The organic layer was dried over anhydrous Na2SO4, and the solvent was removed under vacuum. The residue was recrystallized from a solution of hexane/MeOH (9:1) and kept at −4 °C overnight to allow full precipitation. The solid was filtered and dried under vacuum to afford the pure O-alkylated products 4a–l and 4p–r. Compounds 4m–o were purified through column chromatography (silica gel) using hexane and ethyl acetate (95:5) as the eluent.

2-(Methylthio)-4-(((4-phenyl-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4a)

Light yellow solid (1.19 g, 89% yield), m. p.: 121–122 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.13 (d, 2H, J = 7.2 Hz), 7.77 (s, 1H), 7.60 (s, 1H), 7.59–7.57 (m, 1H), 7.55 (t, 2H, J = 7.5 Hz), 5.66 (s, 2H), 2.61 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 169.7, 168.2, 164.8, 158.6 (q, 2JC-F = 36.2 Hz), 156.5 (q, 2JC-F = 36.4 Hz), 134.9, 132.6, 129.3, 127.6, 120.3 (q, 1JC-F = 275.6 Hz), 120.2 (q, 1JC-F = 275.3 Hz), 108.7 (q, 3JC-F = 2.6 Hz), 107.2 (q, 3JC-F = 2.7 Hz), 68.7, 14.2. 19F NMR (564 MHz, CDCl3): δ (ppm) −70.08, −70.15. HRMS (ESI+) calcd for: C18H13F6N4OS (M + H) 447.0714, found: 447.0725.

2-(Methylthio)-4-(((4-(4-methylphenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4b)

Light brown solid (1.21 g, 88% yield), m.p.: 111–113 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.03 (d, 2H, J = 8.2 Hz), 7.73 (s, 1H), 7.60 (s, 1H), 7.34 (d, 2H, J = 8.1 Hz), 5.65 (s, 2H), 2.62 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 169.6, 168.3, 164.8, 158.4 (q, 2JC-F = 36.0 Hz), 156.5 (q, 2JC-F = 36.1 Hz), 143.4, 132.1, 130.0, 127.5, 120.3 (q, 1JC-F = 275.3 Hz), 120.2 (q, 1JC-F = 275.6 Hz), 108.7 (q, 3JC-F = 2.4 Hz), 106.8, 68.6, 21.6, 14.2 HRMS (ESI+) calcd for: C19H15F6N4OS (M + H) 461.0871, found: 461.0895.

2-(Methylthio)-4-(((4-(2-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4c)

Light brown solid (1.27 g, 89% yield), m. p: 143–146 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.12 (s, 1H), 8.08 (dd, 1H, J = 7.8 Hz, 1.8 Hz), 7.60 (s, 1H), 7.52 (m, 1H), 7.12 (td, 1H, J = 7.5 Hz, 1.0 Hz), 7.05 (d, 1H, J = 8.4 Hz), 5.63 (s, 2H), 3.96 (s, 3H), 2.61 (s, 3H).13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.0, 168.5, 168.3, 164.3, 158.6, 157.6 (q, 2JC-F = 35.9 Hz), 156.4 (q, 2JC-F = 36.4 Hz), 133.4, 131.2, 124.2, 121.3, 120.5 (q, 1JC-F = 278.9 Hz), 120.3 (q, 1JC-F = 275.5 Hz), 112.2 (q, 3JC-F = 2.7 Hz), 111.7, 108.7 (q, 3JC-F = 2.4 Hz), 68.5, 55.7, 14.2.19F NMR (564 MHz, CDCl3): δ (ppm) −69.95, −70.14. HRMS (ESI+) calcd for: C19H15F6N4O2S (M + H) 477.0820, found: 477.0822.

2-(Methylthio)-4-(((4-(3-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4d)

White solid (1.40 g, 98% yield), m. p.:.: 84–85 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 7.74 (s, 1H), 7.67 (d, 2H, J = 7.2 Hz), 7.59 (s, 1H), 7.45 (t, 1H, J = 8.0 Hz), 7.13–7.12 (m, 1H), 5.65 (s, 2H), 3.90 (s, 3H), 2.61 (s, 3H).13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 169.6, 168.2, 164.8, 160.3, 158.8 (q, 2JC-F = 36.2 Hz), 156.5 (q, 2JC-F = 36.4 Hz), 136.3, 130.3, 120.3 (q, 1JC-F = 275.6 Hz), 120.2 (q, 1JC-F = 275.3 Hz), 120.0, 118.3, 112.7, 108.6 (q, 3JC-F = 2.5 Hz), 107.4 (q, 3JC-F = 2.7 Hz), 68.6, 55.6, 14.2.19F NMR (564 MHz, CDCl3): δ (ppm) −70.07, −70.15. HRMS (ESI+) calcd for: C19H15F6N4O2S (M + H) 477.0820, found: 477.0852.

2-(Methylthio)-4-(((4-(4-methoxyphenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4e)

Dark yellow solid (1.31 g, 92% yield), m. p.: 102–104 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.11 (d, 2H, J = 8.9 Hz), 7.68 (s, 1H), 7.59 (s, 1H), 7.03 (d, 2H, J = 8.9 Hz), 5.64 (s, 2H), 3.91 (s, 3H), 2.62 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 174.1, 169.1, 168.4, 164.8, 163.4, 158.2 (q, 2JC-F = 36.0 Hz), 156.5 (q, 2JC-F = 36.4 Hz), 129.4, 127.3, 120.4 (q, 1JC-F = 270.9 Hz), 120.3 (q, 1JC-F = 279.9 Hz), 114.6, 108.7 (q, 3JC-F = 2.7 Hz), 106.3 (q, 3JC-F = 2.7 Hz), 68.6, 55.6, 14.2. 19F NMR (376 MHz, CDCl3): δ (ppm) −70.16, −70.17. HRMS (ESI+) calcd for: C19H15F6N4O2S (M + H) 477.0820, found: 477.0844.

2-(Methylthio)-4-(((4-(4-fluorophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4f)

Dark yellow solid (1.25 g, 90% yield), m. p.: 111–112 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.16 (dd, 2H, J = 8.8 Hz, J = 5.3 Hz), 7.72 (s, 1H), 7.59 (s, 1H), 7.23 (t, 2H, J = 8.5 Hz), 5.65 (s, 2H), 2.62 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.2, 168.1, 165.6 (d, J = 254.6 Hz), 164.8, 158.7 (q, 2JC-F = 36.3 Hz), 156.3 (q, 2JC-F = 36.4 Hz), 131.1 (d, J = 3.1 Hz), 129.9 (d, J = 9.1 Hz), 120.3 (q, 1JC-F = 275.5 Hz), 120.2 (q, 1JC-F = 275.3 Hz), 116.5 (d, J = 22.0 Hz), 108.7 (q, 3JC-F = 2.6 Hz), 106.9 (q, 3JC-F = 2.6 Hz), 68.7, 14.2. 19F NMR (564 MHz, CDCl3): δ (ppm) −70.13, −70.18, −106.26. HRMS (ESI+) calcd for: C18H12F7N4OS (M + H) 465.0620, found: 465.0623.

2-(Methylthio)-4-(((4-(4-chlorophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4g)

Light yellow solid (1.24 g, 86% yield), m. p.: 92–93 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.08 (d, 2H, J = 8.7 Hz), 7.73 (s, 1H), 7.59 (s, 1H), 7.52 (d, 2H, J = 8.7 Hz), 5.65 (s, 2H), 2.62 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 174.2, 168.5, 168.0, 164.9, 158.9 (q, 2JC-F = 36.3 Hz), 156.5 (q, 2JC-F = 36.5 Hz), 139.0, 133.3, 129.6, 128.9, 120.3 (q, 1JC-F = 275.6 Hz), 120.2 (q, 1JC-F = 275.3 Hz), 108.7 (q, 3JC-F = 2.6 Hz), 107.0 (q, 3JC-F = 2.7 Hz), 68.7, 14.2. 19F NMR (376 MHz, CDCl3): δ (ppm) −70.10, −70.17. HRMS (ESI+) calcd for: C18H12ClF6N4OS (M + H) 481.0324, found: 481.0354.

2-(Methylthio)-4-(((4-(4-bromophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4h)

White solid (1.46 g, 93% yield), m. p.: 78–79 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.01 (d, 2H, J = 8.6 Hz), 7.73 (s, 1H), 7.69 (d, 2H, J = 8.6 Hz), 5.65 (s, 2H), 2.62 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.2, 168.6, 168.0, 164.9, 158.9 (q, 2JC-F = 36.4 Hz), 156.5 (q, 2JC-F = 36.4 Hz), 133.7, 132.6, 129.0, 127.6, 120.3 (q, 1JC-F = 275.6 Hz), 120.2 (q, 1JC-F = 275.3 Hz), 108.6 (q, 3JC-F = 2.6 Hz), 107.0 (q, 3JC-F = 2.6 Hz), 68.7, 14.2.19F NMR (564 MHz, CDCl3): δ (ppm) −70.08, −70.15. HRMS (ESI+) calcd for: C18H12BrF6N4OS (M + H) 524.9819, found: 524.9891.

2-(Methylthio)-4-(((4-(4-nitrophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4i)

Light yellow solid (1.28 g, 87% yield), m. p.: 62–64 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.40 (d, 2H, J = 8.8 Hz), 8.33 (d, 2H, J = 8.9 Hz), 7.84 (s, 1H), 7.59 (s, 1H), 5.68 (s, 2H), 2.61 (s, 3H).13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.3, 167.7, 167.3, 165.0, 159.5 (q, 2JC-F = 36.7 Hz), 156.5 (q, 2JC-F = 36.4 Hz), 150.1, 140.4, 128.7, 124.4, 120.3 (q, 1JC-F = 275.5 Hz), 120.0 (q, 1JC-F = 275.5 Hz), 108.6 (q, 3JC-F = 2.6 Hz), 107.9 (q, 3JC-F = 2.6 Hz), 68.9, 14.3. 19F NMR (564 MHz, CDCl3): δ (ppm) −70.01, −70.17. HRMS (ESI+) calcd for: C18H12F6N5O3S (M + H) 492.0565, found: 492.0586.

2-(Methylthio)-4-(((4-(naphthalen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4j)

Yellow solid (1.40 g, 94% yield), m. p.: 140–141 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.65 (s, 1H), 8.17 (d, 1H, J = 8.6 Hz), 8.01 (d, 1H, J = 7.9 Hz), 7.99 (d, 1H, J = 8.7 Hz), 7.92–7.90 (m, 2H), 7.63 (s, 1H), 7.61–7.57 (m, 2H), 5.70 (s, 2H), 2.63 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 169.7, 168.2, 164.9, 158.6 (q, 2JC-F = 36.2 Hz), 156.5 (q, 2JC-F = 36.4 Hz), 135.3, 133.0, 132.1, 129.3, 129.2, 128.6, 128.4, 127.8, 127.1, 123.6, 120.3 (q, 1JC-F = 275.2 Hz), 120.2 (q, 1JC-F = 275.5 Hz), 108.7, 107.4, 68.7, 14.2.19F NMR (564 MHz, CDCl3): δ (ppm) −70.02, −70.12. HRMS (ESI+) calcd for: C22H15F6N4OS (M + H) 497.0871, found: 497.0953.

2-(Methylthio)-4-(((4-(thien-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4k)

White solid (1.22 g, 90% yield), m. p.: 97–99 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 7.89 (dd, 1H, J = 3.8 Hz; J = 0.9 Hz), 7.64 (dd, 1H, J = 5.0 Hz, J = 0.9 Hz), 7.57 (s, 2H), 7.21 (dd, 1H, J = 4.9 Hz, J = 3.9 Hz), 5.60 (s, 2H), 2.61 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 168.1, 164.6, 164.1, 158.3 (q, 2JC-F = 36.3 Hz), 156.4 (q, 2JC-F = 36.4 Hz), 140.5, 132.5, 129.9, 128.9, 120.3 (q, 1JC-F = 275.6 Hz), 120.2 (q, 1JC-F = 275.3 Hz), 108.7 (q, 3JC-F = 2.4 Hz), 105.8 (q, 3JC-F = 2.7 Hz), 68.7, 14.2. 19F NMR (564 MHz, CDCl3): δ (ppm) −70.15, −70.27. HRMS (ESI+) calcd for: C16H11F6N4OS2 (M + H) 453.0278, found: 453.0290.

2-(Methylthio)-4-(((4-(furan-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (4l)

Light brown solid (1.12 g, 86% yield), m. p.: 108–110 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 7.68 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.42 (d, 1H, J = 3.3 Hz), 6.65 (m, 1H), 5.61 (s, 2H), 2.61 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 168.2, 164.7, 160.2, 158.4 (q, 2JC-F = 36.3 Hz) 156.5 (q, 2JC-F = 36.4 Hz), 150.5, 146.7, 120.7 (q, 1JC-F = 275.1 Hz), 120.3 (q, 1JC-F = 275.4 Hz), 115.2, 113.2, 108.7 (q, 3JC-F = 2.2 Hz), 105.5 (q, 3JC-F = 2.3 Hz), 68.6, 14.2. HRMS (ESI+) calcd for: C16H11F6N4O2S (M + H) 437.0507, found: 437.0505.

4-Methyl-2-((2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)methoxy)-6-(trifluoromethyl)pyrimidine (4m)

Yellow solid (0.80 g, 70% yield), m. p.: 41–42 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.55 (s, 1H), 7.24 (s, 1H), 5.58 (s, 2H), 2.62 (s, 3H), 2.60 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.1, 173.9, 168.2, 164.5, 157.4 (q, 2JC-F = 36.3 Hz), 156.5 (q, 2JC-F = 36.3 Hz), 120.3 (q, 1JC-F = 275.6 Hz), 120.2 (q, 1JC-F = 275.1 Hz), 111.4 (q, 3JC-F = 2.7 Hz), 108.6 (q, 3JC-F = 2.6 Hz), 68.5, 24.6, 14.2. 19F NMR (376 MHz, CDCl3): δ (ppm) −70.21, −70.26. HRMS (ESI+) calcd for: C13H11F6N4OS (M + H) 385.0558, found: 385.0595.

4-Isobutyl-2-((2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)methoxy)-6-(trifluoromethyl)pyrimidine (4n)

Yellow oil, 0.92 g (72% yield). 1H NMR (CDCl3, 400 MHz): 7.53 (s, 1H), 7.18 (s, 1H), 5.57 (s, 2H), 2.69 (d, 2H, J = 7.2 Hz), 2.60 (s, 3H), 2.15 (non, 1H, J = 6.8 Hz), 0.95 (d, 6H, J = 6.7 Hz).13C NMR{1H} (CDCl3, 100 MHz): 177.0, 174.0, 168.2, 164.5, 157.41 (q, 2JC-F= 36.3 Hz), 156.4 (q, 2JC-F= 36.3 Hz), 120.3 (q, 1JC-F= 275.5 Hz), 120.2 (q, 1JC-F= 275.3 Hz), 111.3 (q, 3JC-F= 2.8 Hz), 108.6 (q, 3JC-F= 2.6 Hz), 68.5, 47.1, 28.5, 22.3 (2C), 14.2.19F NMR (CDCl3, 376 MHz): −70.11, −70.19. HRMS (ESI–) C16H15F6N4OS calcd. For: 425.0871 (M-H), found: 425.0867.

4-(Tert-butyl)-2-((2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)methoxy)-6-(trifluoromethyl)pyrimidine (4o)

Light yellow oil, 1.20 g (94% yield). 1H NMR (CDCl3, 400 MHz): 7.53 (s, 1H), 7.35 (s, 1H), 5.57 (s, 2H), 2.60 (s, 3H), 1.35 (s, 9H). 13C NMR{1H} (CDCl3, 125 MHz): 184.8, 174.1, 168.3, 164.2, 158.1 (q, 2JC-F= 36.1 Hz), 156.4 (q, 2JC-F= 36.4 Hz), 120.3 (2C, q, 1JC-F= 275.4 Hz), 108.7 (q, 3JC-F= 2.8 Hz), 107.2 (q, 3JC-F= 2.8 Hz), 68.5, 38.5, 29.2, 14.2. 19F NMR (CDCl3, 376 MHz): −69.96, −70.20. HRMS (ESI–) C16H15F6N4OS calcd. For: 425.0871 (M-H); Found: 425.0888.

2-(Methylthio)-4-(((4-phenyl-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trichloromethyl)pyrimidine (4p)

Light brown solid (1.35 g, 91% yield), m. p.: 115–116 °C.1H NMR (600 MHz, CDCl3): δ (ppm) 8.13 (d, 2H, J = 7.2 Hz), 7.85 (s, 1H), 7.76 (s, 1H), 7.59 (t, 1H, J = 7.3 Hz), 7.55 (t, 2H, J = 7.4 Hz), 5.67 (s, 2H), 2.64 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 173.1, 169.7, 168.0, 166.7, 164.9, 158.6 (q, 2JC-F = 36.2 Hz), 134.9, 132.5, 129.2, 127.6, 120.3 (q, 1JC-F = 275.3 Hz), 107.7, 107.1 (q, 3JC-F = 2.5 Hz), 95.7, 68.9, 14.3.19F NMR (564 MHz, CDCl3): δ (ppm) −70.03. HRMS (ESI+) calcd for: C18H13Cl3F3N4OS (M + H) 494.9827, found: 494.9859.

2-(Methylthio)-4-(((4-(4-chlorophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trichloromethyl)pyrimidine (4q)

White solid, (1.55 g, 98% yield), m. p.: 92–95 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.09 (d, 2H, J = 8.6 Hz), 7.84 (s, 1H), 7.72 (s, 1H), 7.52 (d, 2H, J = 8.6 Hz), 5.66 (s, 2H), 2.64 (s, 3H).13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 173.2, 168.4, 167.8, 166.8, 165.0, 158.9 (q, 2JC-F = 36.3 Hz), 139.0, 133.3, 129.6, 129.6, 128.9, 120.2 (q, 1JC-F = 275.4 Hz), 107.6, 106.9 (q, 3JC-F = 2.6 Hz), 95.6, 68.9, 14.3. 19F NMR (564 MHz, CDCl3): δ (ppm) −70.05. HRMS (ESI+) calcd for: C18H12Cl4F3N4OS (M + H) 528.9438, found: 528.9492.

2-(Methylthio)-4-(((4-(4-bromophenyl)-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trichloromethyl)pyrimidine (4r)

White solid, (1.68 g, 98% yield), m. p.: 111–113 °C.1H NMR (600 MHz, CDCl3): δ (ppm) 8.01 (d, 2H, J = 8.5 Hz), 7.84 (s, 1H), 7.73 (s, 1H), 7.68 (d, 2H, J = 8.6 Hz), 5.56 (s, 2H), 2.64 (s, 3H).13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 173.2, 168.5, 167.8, 166.8, 165.0, 158.9 (q, 2JC-F = 36.3 Hz), 133.8, 132.5, 129.0, 127.5, 120.2 (q, 1JC-F = 275.4 Hz), 107.6, 106.9 (q, 3JC-F = 2.7 Hz), 95.6, 68.9, 14.3.19F NMR (564 MHz, CDCl3): δ (ppm) −70.06. HRMS (ESI+) calcd for: C18H12BrCl3F3N4OS (M + H) 572.8933, found: 572.8987.

General procedure for the synthesis of 4-(Iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines 6c–d

To a round-bottom flask loaded with 5-bromo-1,1,1-trihalo-4-methoxypent-3-en-2-ones 5a (halo = F, 100 mmol, 24.7 g) or 5b (halo = Cl, 100 mmol, 29.6 g), H2O (100 mL), MeOH (250 mL), and 2-methylisothiourea sulfate (200 mmol, 55.6 g) were added, and the reaction mixture was stirred for 15 min. After this period, conc. HCl (30 mL) was added, and the mixture was heated to reflux under vigorous stirring for a period of 48 h. After the reaction time, the mixture was allowed to cool to r.t. and then was extracted with CH2Cl2 (3× 150 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under vacuum. The residue was dissolved in acetone (150 mL), and KI (125 mmol, 20.75 g) was added in small portions under vigorous stirring. The reaction was continued under stirring for 8 h at r.t., and after this period, the solvent was removed under vacuum, and the residue was dissolved in CH2Cl2 (150 mL), washed with saturated solution of Na2S2O3 (2×, 50 mL) and H2O (2× 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel) using hexanes/ethyl acetate (90:10) as the eluent. 4-(Iodomethyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine 6c was obtained in 65% yield, and 4-(iodomethyl)-2-(methylthio)-6-(trichloromethyl)pyrimidine 6d was obtained in 62% yield and was already reported previously.43

4-(Iodomethyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (6c)

Yellow oil (21.71 g, 65% yield) 1H NMR (400 MHz, CDCl3): δ (ppm) 7.30 (s, 1H), 4.38 (s, 2H), 2.60 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 174.6, 169.5, 156.4 (q, 2JC-F = 36.4 Hz) 120.1 (q, 1JC-F = 275.4 Hz), 110.4 (q, 3JC-F = 2.74 Hz), 14.3, 1.93. 19F NMR (376 MHz, CDCl3): δ (ppm) −70.34. HRMS (ESI+) calcd for: C7H7F3IN2OS (M + H) 334.9326, found: 334.9340.

General Procedure for the Oxidation of 4a Using m-CPBA

To a round-bottom flask loaded with 2-(methylthio)-4-(((4-phenyl-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (2 mmol, 0.896 g) 4a dissolved in CHCl3 (20 mL), m-chloroperbenzoic acid (4 mmol, 0.690 g) was added. The mixture was kept for 16 h under vigorous stirring at r.t. After this time, it was washed with H2O (3× 15 mL), and the organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum to provide pure sulfone 7.

2-(Methylsulfonyl)-4-(((4-phenyl-6-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-6-(trifluoromethyl)pyrimidine (7)

White solid (0.87 g, 91% yield), m. p.: 154–155 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 8.26 (s, 1H) 8.14 (d, 2H, J = 7.3 Hz), 7.81 (s, 1H), 7.61 (t, 1H, J = 7.2 Hz), 7.57 (t, 2H, J = 7.4 Hz), 5.90 (s, 2H), 3.45 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 171.9, 170.0, 166.3, 164.4, 158.8 (q, 2JC-F = 36.4 Hz), 157.7 (q, 2JC-F = 38.1 Hz), 134.6, 132.8, 129.4, 127.6, 120.2 (q, 1JC-F = 275.3 Hz), 119.7 (q, 1JC-F = 276.0 Hz), 116.7 (q, 3JC-F = 2.4 Hz), 107.6 (q, 3JC-F = 2.6 Hz), 68.4, 39.1. 19F NMR (564 MHz, CDCl3): δ (ppm) −69.29, 70.06. HRMS (ESI+) calcd for: C18H13F6N4O3S (M + H) 479.0612, found: 479.0606.

Acknowledgments

The authors are grateful for the financial support from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS)—FAPERGS/CNPq—PRONEX, grant no. 16/2551-0000477-3, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant no. 407898/2018-2), as well as the fellowships from Deutscher Akademischer Austauschdienst (DAAD, M.M., program no. 57507869, grant no. 91793237), Cooordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, M. M.; G. S. P.), and CNPq (H. G. B.; M. A. P. M.; N. Z.).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c01925.

  • 1H, 13C{1H}, and 19F NMR spectra of compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c01925_si_001.pdf (4.3MB, pdf)

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