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Article

Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors

by
Ying Huang
1,2,3,
Tingyu Zhu
1,2,3,
Yinghua Li
1,* and
Deguang Huang
1,*
1
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, University of Chinese Academy of Sciences, Fuzhou 350002, China
2
College of Chemistry and Materials Science, Fujian Normal University, Fuzhou 350007, China
3
Fujian College, University of Chinese Academy of Sciences, Fuzhou 350002, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(16), 3723; https://doi.org/10.3390/molecules29163723
Submission received: 17 July 2024 / Revised: 31 July 2024 / Accepted: 1 August 2024 / Published: 6 August 2024
(This article belongs to the Special Issue Organic Synthesis and Application of Bioactive Molecules)
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Abstract

:
A base-induced synthesis of 2-(4-(2-(phenylthio)ethyl)piperazinyl) acetonitriles by reaction of disulfides, 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride and trimethylsilyl cyanide is reported. The scope of the method is demonstrated with 30 examples. The reaction mechanism research indicates that the three-component reaction would be a SN2 reaction. The products exhibit good activities towards advanced synthesis of aqueous soluble acyl-CoA: cholesterol O-acyltransferase-1 (ACAT-1) inhibitors. Our work is superior as it uses less-odor disulfides as carbon sources and EtOH as solvent in a water and dioxygen insensitive reaction system, followed by a simple purification process.

Graphical Abstract

1. Introduction

The incorporation of piperazine into medicinal molecules is proved effective in the increase in aqueous solubility and therefore in the improvement of oral absorption and bioavailability. It is of high importance in medication safety for further development of clinical candidates. Sulfur-containing ethyl piperazine compounds and their derivatives (Figure 1) are important building blocks in pharmaceuticals. Their biochemical activities were discovered and explored in the treatment of cancer [1], glioblastoma [2,3], atherosclerosis [4], anxiety neurosis [5] and the reduction of blood pressure [6]. The 2-mercaptobenzimidazole bound ethyl piperazine is recognized as a targeting moiety for the structural accommodation of 2-(4-(2-((1H-Benzo[d]imidazol-2-yl)thio)-ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis(methylthio)-pyridin-3-yl)acetamide hydrochloride [K-604], an acyl-CoA: cholesterol O-acyltransferase-1 (ACAT-1) inhibitor (Figure 1d). The enzymes catalyze cholesterol esterification with acylcoenzyme A [7]. They have received attention as promising drug targets for the treatment of diseases such as hyperlipidemia [8], neurodegenerative disease [9,10,11,12,13,14], cancer [15,16], leukemia [17], and bleomycin-induced lung injury [18].
Sulfur-containing ethyl piperazine compounds were originally obtained by introducing thiol groups on the side chain of the 4-substituted 1-(2-chloroethyl)piperazine or 1-(2-hydroxyethyl) piperazine via nucleophilic substitution reactions [8,19,20,21,22] (Scheme 1). A ring-opening method was developed using cyclic tertiary amines as the ethyl piperazine source enabled by the incorporation of thiolates through facile C-N bond cleavage. Reaction of aromatic halogenated compounds with triethylenediamine (DABCO) in the presence of Na2S as the sulfur source at 120 °C afforded the products 1-(2-(pyridin-2-yl)ethyl)-4-(pyridin-2-yl)piperazines in considerable yields [23] (Scheme 1b). Similar products were obtained by reaction of either o-silyl aryl triflates or pyridine-N-oxides with thiolates in the presence of CsF or trifluoroacetic anhydride as the activating agent, respectively [24,25]. The method was extended using 1-alkyl group bound 4-aza-1-azoniabicyclo[2.2.2]octane as the ethyl piperazine source under alkaline conditions [26,27,28,29]. Although significant advances have been made, the synthesis of sulfur-containing ethyl piperazine compounds is of interest to scientists. Up to now, almost all the works concerning the building of the sulfur-containing ethyl piperazine skeleton have said that the C-N bond cleavage of the cyclic tertiary amines was achieved in two steps: quaternization first, ring-opening second. Synthesis of the sulfur-containing ethyl piperazine compound by a SN2 reaction was rarely reported.
Molecules 29 03723 g001
Figure 1. Representative bioactive sulfur-containing ethyl piperazine compounds (a) [23], (b) [6], (c) [1], and (d) [8,20].
Figure 1. Representative bioactive sulfur-containing ethyl piperazine compounds (a) [23], (b) [6], (c) [1], and (d) [8,20].
Molecules 29 03723 g001
To date, there are mainly two routes to prepare the sulfur-containing ethyl piperazine compound [K-604] and its derivatives [8,20,30,31,32] (Scheme 2). The non-tertiary amine 1-(2-hydroxyethyl)piperazine was employed as the starting material in the routes, and the target product was prepared by multi-step reactions. Interestingly, the tertiary amine 4-aza-1-azoniabicyclo[2.2.2]octane has not been used for the synthesis of ACAT-1 inhibitors. Therefore, we report here a simple and eco-friendly method for the synthesis of various 2-(4-(2-(phenylthio)ethyl)piperazinyl)acetonitriles (2) by a three-component SN2 disubstitution reaction, using 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride (CAABC) as the ethyl piperazine source, disulfide as the thiol source, trimethylsilyl cyanide (TMSCN) as the cyanide source, and EtOH as the solvent. The products were easily obtained by a simple purification process. They can be applied to the preparation of [K-604] and its derivatives in two steps.

2. Results and Discussion

Reaction of diphenyl disulfide (1a, 0.1 mmol), CAABC (0.2 mmol), TMSCN (0.22 mmol) and Cs2CO3 (0.6 mmol) under air atmosphere in EtOH (1 mL) for 3 h at 100 °C provided the product 2-(4-(2-(phenylthio)ethyl)piperazinyl)acetonitrile (2a) in 90% yield (based on diphenyl disulfide, Table 1, entry 1). Other alkali salts, such as K2CO3, Na2CO3, KOH, and tBuOK, afforded the product in lower yields (entries 2–5). The addition of a trace of water had little effect on production, but a greater amount of water (7:3) would lead to the generation of 2a in a lower yield (entry 6). Only a trace of product could be found when the reaction was performed in a clear aqueous solution (entry 7). The use of MeOH as the solvent provided 2a in 75% yield (entry 8). With other polar solvents, such as DMF and DMSO, no corresponding product could be obtained (entries 9 and 10). Higher temperature would not help to improve the yield, while a lower temperature would decrease the reaction (entries 11 and 12). A period of 3 h would be enough for the completeness of the reaction. A longer or shorter time is of no advantage to the reaction (entries 13 and 14).
At the optimized conditions, the scope of the substrates was investigated for the production of 2 (Figure 2). Thirty compounds were prepared in terms of the electronic effect and steric effect of the functional groups on the substrates. It was found that both the electron-donating groups and the electron-withdrawing groups on the benzene ring of diphenyl sulfides would lead to the reduction of yields. By contrast, the electron-donating groups (2b–2d) might have a larger effect than the electron-withdrawing groups (2e–2g), except for the strong electron-withdrawing groups CF3 by which the yield decreased dramatically, down to 61%. This inference was consistent with the experimental results obtained from the comparison of compounds 2i and 2j with 2k–2m, and 2n and 2o with 2p–2r. The influence of steric hindrance on the reaction was studied by the employment of methoxyl-(2b, 2i and 2n), methyl-(2d, 2j and 2o), Br-(2e, 2k and 2p), Cl-(2f, 2l and 2q), and F-(2g, 2m and 2r) groups at the para, meta, and ortho positions of the benzene rings. The results showed that the steric effect had little impact on the production of the target products. It was in accordance with the reaction of the disubstituted diphenyl disulfide under the same conditions (2s–2u, 74–78%). Our reaction exhibited good compatibility with other cyclic thiol sources, such as 2-naphthalenethiol (2v), 2-mercaptopyridine (2w), thiophenethiol (2x), 2-methyl-3-furanthiol (2y), 2-benzothiazolethiol (2z), 2-benzoxazolethiol (2aa), and 2-mercaptobenzimidazole (2ab). The corresponding products were obtained in yields of 57–84%. In addition, the reaction of n-hexyl disulfide (2ac) or diphenyl diselenide (2ad) under the standard conditions also produced the desired products in yields of 51% and 80%, respectively. These results implicate a relatively broad range of substrates in our reaction. In addition, the synthetic utility of reaction was checked by performing the experiments on the gram scale. The reaction of diphenyl disulfide (1a) and CAABC on a 1.5 g scale produced compound 2a in 90% yield (Supporting Information, Section S2.4), which implies that the amount of the starting material did not directly influence the quality of reaction, and our reaction was suitable for the production of sulfur-containing ethyl piperazine compounds for further synthesis.
With the progress of research on compounds 2, a number of experiments were conducted to study the reaction mechanism. The reaction of diphenyl disulfide (1a) with CAABC, TMSCN and Cs2CO3 under N2 atmosphere in EtOH afforded the product 2a in 91% yield (Scheme 3a). The reaction of thiophenol with CAABC and TMSCN under the standard conditions also provided the product 2a in similar yield (Scheme 3b). It meant that the reaction was independent of dioxygen and the thiophenol could be an intermediate of reaction. Compound 3a was obtained when the reaction was repeated in the absence of TMSCN. The result was checked using TMSCF3 and Et4NCN as the nucleophiles. The reaction of 1a, CAABC and TMSCF3 under the standard conditions afforded 3a in a similar yield. With the replacement of TMSCF3 by Et4NCN, compound 2a was obtained in 60% yield. It indicated that cyanide anion was the right nucleophile for the substitution of the chloride group, and the chloromethyl group might work as a leaving group without the presence of CN−. Meanwhile, the reaction of 1a with 1-(cyanomethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride (CYAABC) produced a piperazine amide compound 4a rather than the desired compound 2a. They seemed to be SN2 reactions with the attack of sulfide (obtained by the reduction of diphenyl disulfide) on the ethylene group of the DABCO ring on one side, and the attack of the hydroxyl ion (generated by the alkalization of H2O in EtOH) on the cyanomethyl groups of the other side. The speculation was supported by the reaction of 1a and TMSCN with triethylenediamine (DABCO) or 1-ethyl-4-aza-1-azonia bicyclo[2.2.2]octane bromide (EAABB), from which no desired product could be observed (Scheme 3e,f). At last, there was no reaction between CAABC and TMSCN under the standard conditions.
Based on the above results, a possible reaction mechanism was proposed in Scheme 4. Diphenyl disulfide is reduced to thiophenolate in the presence of Cs2CO3 in EtOH when heated. The PhS− anion attacks CAABC on the ethylene with the attack of CN− on the chloromethyl group to yield the desired compound 2a.
Our reaction exhibited good tolerance towards the transformation of aromatic thiols and/or disulfides to ACAT-1 inhibitors. Two routes were discovered in this work, one by acylation of compounds 2, the other by cutting the chloromethyl group off from the piperazine (Scheme 5). The stirring of compound 2ab in the presence of KOH under air atmosphere in tBuOH for 3 h at 110 °C afforded compound 4b in 75% yield. Reaction of 4b with 2,6-diisopropylaniline and 6-methyl-2,4-bis(methylthio)pyridin-3-amine provided the desired products 5a and 5b in yields of 10 and 12%, respectively. The poor solubility of 4b in MeCN restricted its application. Other polar solvents, such as MeOH, H2O and DMF, would cause the increase in by-products. Although the method had its disadvantage, it offered a chance to improve the rate of production. The reaction of 2-mercaptobenzimidazole (1ab) with CAABC in the absence of TMSCN under the standard conditions produced compound 3b in 80% yield, which was further reacted with 2-bromo-N-(2,6-diisopropylphenyl)acetamide and 2-bromo-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide to yield compounds 5a and 5b in yields of 60% and 75%. In comparison to what has been described in the literatures, our method is superior in offering fewer reaction steps with a similar yield in EtOH (first step). The structures of compounds were determined by X-ray crystallography and are shown in Figure 3 (2b, 2ab, 3b, 4b, and 5a) and Figure S1 (2w, 2z and 2ab), respectively.

3. Experimental Section

3.1. General Preparations

Chemicals: Unless otherwise stated, all commercial-grade chemicals were used without further purification. 6-Methyl-2,4-bis(methylthio)-pyridin-3-amine, 2-bromo-N-(2,6-diisopropylphenyl) acetamide and 2-bromo-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide were prepared according to the reported methods (see Supporting Information).

3.2. Synthesis Procedures

3.2.1. General Procedure for the Synthesis of Compounds 2

Disulfides 1 (0.1 mmol), 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride (CAABC) (0.2 mmol), trimethylsilyl cyanide (0.22 mmol), Cs2CO3 (0.6 mmol) and EtOH (1 mL) were mixed in a 50 mL Teflon screw-cap sealed tube. The mixture was vigorously stirred under air atmosphere for 3 h at 100 °C (oil bath). After cooling to room temperature, the reaction mixture was filtered. The precipitate was washed with EtOH (2 mL). The organic layers were combined and flashed through a pad of silica gel (3 mL) in pipette eluted with petroleum ether/EtOH (10:1 to 5:1 v/v) (10 mL) to yield the products 2. The yields and the characterization data of products are shown on pages S11–S17; 1H NMR spectra are presented on pages S31–S60 (SI).
2-(4-(2-(phenylthio)ethyl)piperazinyl)acetonitrile (2a): yield, 90% (47.1 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.3 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 3.46 (s, 2H), 3.02 (t, J = 7.2 Hz, 2H), 2.65–2.47 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 136.3, 129.0, 128.97, 126.0, 114.8, 57.4, 52.5, 51.7, 45.9, 30.8. HRMS (ESI) m/z [M + H]+ calcd for C14H20N3S, 262.1372; found, 262.1375.
2-(4-(2-((4-methoxyphenyl)thio)ethyl)piperazinyl)acetonitrile (2b): yield, 76% (44.3 mg); light yellow solid. M.p. 88–89 °C. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 3.76 (s, 3H), 3.46 (s, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.59–2.42 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 159.0, 133.3, 126.1, 114.8, 114.6, 57.7, 55.4, 52.5, 51.7, 45.9, 32.8. HRMS (ESI) m/z [M + H]+ calcd for C15H22N3OS, 292.1484; found, 292.1487.
2-(4-(2-((4-(tert-butyl)phenyl)thio)ethyl)piperazinyl)acetonitrile (2c): yield, 77% (48.9 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.33–7.26 (m, 4H), 3.49 (s, 2H), 3.02 (t, J = 7.2 Hz, 2H), 2.66–2.49 (m, 10H), 1.30 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 149.4, 132.6, 129.3, 126.0, 114.8, 57.5, 52.5, 51.7, 45.9, 34.5, 31.3, 31.2. HRMS (ESI) m/z [M + H]+ calcd for C18H28N3S, 318.2004; found, 318.2007.
2-(4-(2-(p-tolylthio)ethyl)piperazinyl)acetonitrile (2d): yield, 78% (43.0 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 3.46 (s, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.64–2.45 (m, 10H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 136.3, 132.3, 130.0, 114.8, 57.5, 52.5, 51.7, 45.9, 31.4, 21.1. HRMS (ESI) m/z [M + H]+ calcd for C15H22N3S, 276.1534; found, 276.1538.
2-(4-(2-((4-bromophenyl)thio)ethyl)piperazinyl)acetonitrile (2e): yield, 88% (60.0 mg); light yellow solid. M.p. 102–103 °C. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5, 2H), 3.47 (s, 2H), 2.98 (t, J = 7.2, 2H), 2.63–2.48 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 135.6, 132.0, 130.6, 119.8, 114.8, 57.1, 52.5, 51.6, 45.9, 30.9. HRMS (ESI) m/z [M + H]+ calcd for C14H19BrN3S, 340.0483; found, 340.0487.
2-(4-(2-((4-chlorophenyl)thio)ethyl)piperazinyl)acetonitrile (2f): yield, 87% (51.5 mg); white solid. M.p. 91–92 °C. 1H NMR (400 MHz, CDCl3) δ 7.29–7.23 (m, 4H), 3.51 (s, 2H), 3.02 (t, J = 7.2 Hz, 2H), 2.65–2.50 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 134.8, 132.0, 130.5, 129.1, 114.8, 57.2, 52.5, 51.7, 45.9, 31.2. HRMS (ESI) m/z [M + H]+ calcd for C14H19ClN3S, 296.0988; found, 296.0992.
2-(4-(2-((4-fluorophenyl)thio)ethyl)piperazinyl)acetonitrile (2g): yield, 84% (47.0 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8.4, 5.3 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 3.50 (s, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.64–2.35 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 161.7 (d, J = 246.3 Hz), 132.3 (d, J = 8.0 Hz), 131.0 (d, J = 3.3 Hz), 116.1 (d, J = 21.8 Hz), 114.8, 57.4, 52.4, 51.6, 45.8, 32.1. HRMS (ESI) m/z [M + H]+ calcd for C14H19FN3S, 280.1284; found, 280.1287.
2-(4-(2-((4-(trifluoromethyl)phenyl)thio)ethyl)piperazinyl)acetonitrile (2h): yield, 61% (40.2 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz), 3.48 (s, 2H), 3.08 (t, J = 7.3 Hz), 2.68–2.48 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 141.1, 126.3 (q, J = 32.8 Hz), 126.3, 124.7 (q, J = 3.7 Hz), 123.1 (q, J = 271.8 Hz), 113.7, 55.7, 51.4, 50.6, 44.8, 28.9. HRMS (ESI) m/z [M + H]+ calcd for C15H19F3N3S, 330.1252; found, 330.1255.
2-(4-(2-((3-methoxyphenyl)thio)ethyl)piperazinyl)acetonitrile (2i): yield, 68% (39.6 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.84 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 3.75 (s, 3H), 3.46 (s, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.67–2.47 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 159.8, 137.6, 129.8, 120.9, 114.8, 114.3, 111.6, 57.3, 55.3, 52.5, 51.6, 45.8, 30.5. HRMS (ESI) m/z [M + H]+ calcd For C15H22N3OS, 292.1484; found, 292.1487.
2-(4-(2-(m-tolylthio)ethyl)piperazinyl)acetonitrile (2j): yield, 76% (41.9 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.17–7.08 (m, 3H), 6.97 (d, J = 7.0 Hz), 3.47 (s, 2H), 3.01 (t, J = 7.6 Hz, 2H), 2.65–2.48 (m, 10H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 138.7, 135.9, 129.7, 128.8, 126.9, 126.0, 114.8, 57.4, 52.5, 51.7, 45.9, 30.7, 21.4. HRMS (ESI) m/z [M + H]+ calcd for C15H22N3S, 276.1534; found, 276.1538.
2-(4-(2-((3-bromophenyl)thio)ethyl)piperazinyl)acetonitrile (2k): yield, 86% (58.6 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 3.43 (s, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.61–2.44 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 139.0, 131.0, 130.3, 128.9, 127.2, 122.8, 114.8, 57.0, 52.4, 51.6, 45.9, 30.6. HRMS (ESI) m/z [M + H]+ calcd for C14H19BrN3S, 340.0483; found, 340.0487.
2-(4-(2-((3-chlorophenyl)thio)ethyl)piperazinyl)acetonitrile (2l): yield, 85% (50.3 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23–7.21 (m, 1H), 7.13–7.10 (m, 2H), 7.07–7.04 (m, 1H), 3.42 (s, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.61–2.41 (m, 10H). 13C NMR (400 MHz, CDCl3) δ 138.7, 134.6, 130.0, 128.1, 126.6, 125.9, 114.8, 57.0, 52.4, 51.6, 45.9, 30.6. HRMS (ESI) m/z [M + H]+ calcd for C14H19ClN3S, 296.0988; found, 296.0992.
2-(4-(2-((3-fluorophenyl)thio)ethyl)piperazinyl)acetonitrile (2m): yield, 82% (45.8 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (td, J = 8.0, 6.2 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.99 (t, J = 8.4 Hz, 1H), 6.83 (t, J = 8.4 Hz, 1H), 3.48 (s. 2H), 3.03 (t, J = 7.2 Hz, 2H), 2.67–2.44 (m, 10H). 13C NMR (101 MHz, CDCl3) δ162.9 (d, J = 247.9 Hz), 139.0 (d, J = 7.9 Hz), 130.2 (d, J = 8.6 Hz), 124.0 (d, J = 2.9 Hz), 115.1 (d, J = 23.1 Hz), 114.8, 112.7 (d, J = 21.2 Hz), 57.0, 52.5, 51.7, 45.9, 30.5. HRMS (ESI) m/z [M + H]+ calcd for C14H19FN3S, 280.1284; found, 280.1287.
2-(4-(2-((2-methoxyphenyl)thio)ethyl)piperazinyl)acetonitrile (2n): yield, 67% (39.0 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 3.80 (s, 3H), 3.41 (s, 2H), 2.94 (t, J = 7.2 Hz), 2.71–2.29 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 157.4, 129.5, 127.3, 124.2, 121.0, 114.8, 110.5, 57.3, 55.8, 52.5, 51.7, 45.8, 29.2. HRMS (ESI) m/z [M + H]+ calcd for C15H22N3OS, 292.1484; found, 292.1487.
2-(4-(2-(o-tolylthio)ethyl)piperazinyl)acetonitrile (2o): yield, 70% (38.6 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.2 Hz, 1H), 7.19–7.12 (m, 2H), 7.09 (t, J = 7.2 Hz, 1H), 3.50 (s, 2H), 3.02 (t, J = 7.2 Hz), 2.71–2.47 (m, 10H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 137.6, 135.5, 130.2, 127.8, 126.5, 125.8, 114.8, 57.2, 52.5, 51.7, 45.9, 30.1, 20.5. HRMS (ESI) m/z [M + H]+ calcd for C15H22N3S, 276.1534; found, 276.1538.
2-(4-(2-((2-bromophenyl)thio)ethyl)piperazinyl)acetonitrile (2p): yield, 85% (57.8 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.9 Hz, 1H), 7.21–7.18 (m, 2H), 6.99–6.92 (m, 1H), 3.43 (s, 2H), 2.99 (t J = 7.2 Hz, 2H), 2.66–2.44 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 137.8, 133.0, 128.0, 127.9, 126.7, 123.6, 114.8, 56.7, 52.5, 51.6, 45.9, 30.2. HRMS (ESI) m/z [M + H]+ calcd for C16H11N3NaO2, C14H19BrN3S, 340.0483; found, 340.0487.
2-(4-(2-((2-chlorophenyl)thio)ethyl)piperazinyl)acetonitrile (2q): yield, 84% (49.7 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 3.42 (s, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.68–2.41 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 135.7, 133.5, 129.7, 128.4, 127.2, 126.6, 114.8, 56.8, 52.5, 51.7, 45.9, 29.8. HRMS (ESI) m/z [M + H]+ calcd for C14H19ClN3S, 296.0988; found, 296.0992.
2-(4-(2-((2-fluorophenyl)thio)ethyl)piperazinyl)acetonitrile (2r): yield, 79% (44.1 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 7.6 Hz, 1H), 7.20 (dd, J = 13.1, 7.5 Hz, 1H), 7.12–7.00 (m, 2H), 3.48 (s, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.67–2.43 (m, 10H). 13C NMR (101 MHz, CDCl3) δ161.6 (d, J = 245.1 Hz), 132.3 (d, J = 1.8 Hz), 128.5 (d, J = 7.9 Hz), 123.0 (d, J = 17.6 Hz), 115.7 (d, J = 22.5 Hz), 114.8, 57.5, 52.4, 51.7, 45.9, 30.7. HRMS (ESI) m/z [M + H]+ calcd for C14H19FN3S, 280.1284; found, 280.1287.
2-(4-(2-((2,4-dimethylphenyl)thio)ethyl)piperazinyl)acetonitrile (2s): yield, 75% (43.4 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 3.49 (s, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.65–2.50 (m, 10H), 2.35 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 138.3, 136.1, 131.6, 131.2, 129.4, 127.2, 114.8, 57.4, 52.5, 51.7, 45.9, 30.8, 20.9, 20.5. HRMS (ESI) m/z [M + H]+ calcd for C16H24N3S, 290.1691; found, 290.1694.
2-(4-(2-((2,5-dimethylphenyl)thio)ethyl)piperazinyl)acetonitrile (2t): yield, 74% (42.8 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 3.48 (s, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.67–2.51 (m, 10H), 2.32 (s, 3H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 136.0, 135.1, 134.6, 130.0, 128.7, 126.6, 114.8, 57.2, 52.5, 51.7, 45.9, 30.2, 21.1, 20.0. HRMS (ESI) m/z [M + H]+ calcd for C16H24N3S, 290.1691; found, 290.1694.
2-(4-(2-((3,5-dimethylphenyl)thio)ethyl)piperazinyl)acetonitrile (2u): yield, 78% (45.2 mg); light yellow iol. 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 2H), 6.78 (s, 1H), 3.47 (s, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.65–2.46 (m, 10H), 2.26 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 138.5, 135.7, 127.9, 126.7, 114.8, 57.5, 52.5, 51.7, 45.9, 30.7, 21.3. HRMS (ESI) m/z [M + H]+ calcd for C16H24N3S, 290.1691; found, 290.1694.
2-(4-(2-(naphthalen-2-ylthio)ethyl)piperazinyl)acetonitrile (2v): yield, 57%, (35.5 mg), light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.79–7.70 (m, 4H), 7.49–7.39 (m, 3H), 3.46 (s, 2H), 3.13 (t, J = 7.6 Hz, 2H), 2.71–2.48 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 133.8, 131.7, 128.5, 127.8, 127.3, 127.1, 126.7, 125.7, 114.8, 57.3, 52.5, 51.7, 45.9, 30.7. HRMS (ESI) m/z [M + H]+ calcd for C18H22N3S, 312.1534; found, 312.1538.
2-(4-(2-(pyridin-2-ylthio)ethyl)piperazinyl)acetonitrile (2w): yield, 84% (44.1 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 4.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 5.6 Hz, 1H), 3.50 (s, 2H), 3.31 (t, J = 7.3 Hz, 2H), 2.74–2.66 (m, 2H), 2.61 (br s, 8H). 13C NMR (101 MHz, CDCl3) δ 158.6, 149.4, 135.9, 122.2, 119.4, 114.9, 57.5, 52.4, 51.6, 45.8, 26.9. HRMS (ESI) m/z [M + H]+ calcd for C13H19N4S, 263.1331; found, 263.1334.
2-(4-(2-(thiophen-2-ylthio)ethyl)piperazinyl)acetonitrile (2x): yield, 76% (40.6 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 5.3 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 6.95 (dd, J = 5.3, 3.6 Hz, 1H), 3.48 (s, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.64–2.45 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 134.2, 133.7, 129.3, 127.6, 114.8, 57.5, 52.5, 51.7, 45.9, 35.8. HRMS (ESI) m/z [M + H]+ calcd For C12H18N3S2, 268.0942; found, 268.0946.
2-(4-(2-((2-methylfuran-3-yl)thio)ethyl)piperazinyl)acetonitrile (2y): yield, 45% (23.9 mg); light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 1.8 Hz, 1H), 3.43 (s, 2H), 2.66 (t, J = 7.2 Hz, 2H), 2.57–2.41 (m, 10H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.9, 140.6, 115.0, 114.7, 110.0, 57.9, 52.5, 51.7, 45.9, 32.8, 11.9. HRMS (ESI) m/z [M + H]+ calcd for C13H20N3OS, 266.1327; found, 266.1331.
2-(4-(2-(benzo[d]thiazol-2-ylthio)ethyl)piperazinyl)acetonitrile (2z): yield, 60% (38.2 mg); light yellow solid. M.p. 77–78 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 3.44 (t, J = 7.1 Hz, 2H), 3.42 (s, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.54 (br s, 8H). 13C NMR (101 MHz, CDCl3) δ 167.0, 153.2, 135.2, 126.1, 124.3, 121.4, 121.0, 114.8, 56.7, 52.4, 51.7, 45.9, 30.8. HRMS (ESI) m/z [M + H]+ calcd for C15H19N4S2, 319.1051; found, 319.1055.
2-(4-(2-(benzo[d]oxazol-2-ylthio)ethyl)piperazinyl)acetonitrile (2aa): yield, 68% (41.1 mg); light yellow solid. M.p. 57–58 °C. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.17 (tt, J = 7.5, 6.4 Hz, 2H), 3.41 (s, 2H), 3.38 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.54 (br s, 8H). 13C NMR (101 MHz, CDCl3) δ 165.2, 151.8, 141.9, 124.3, 123.9, 118.3, 114.8, 109.9, 56.5, 52.3, 51.7, 45.9, 30.0. HRMS (ESI) m/z [M + H]+ calcd for C15H19N4OS, 303.1280; found, 303.1283.
2-(4-(2-((1H-benzo[d]imidazol-2-yl)thio)ethyl)piperazinyl)acetonitrile (2ab): yield, 71% (42.8 mg); light yellow solid. M.p. 139–140 °C. 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 7.54 (dd, J = 6.0, 3.2 Hz, 2H), 7.10 (dd, J = 6.0, 3.2 Hz, 2H), 3.48 (s, 2H), 3.14 (t, J = 5.2 Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H), 2.63 (br s, 8H). 13C NMR (101 MHz, CDCl3) δ 151.0, 139.7, 122.1, 114.7, 114.3, 60.0, 52.8, 51.4, 45.8, 29.7. HRMS (ESI) m/z [M + H]+ calcd for C15H20N5S, 302.1439; found, 302.1443.
2-(4-(2-(hexylthio)ethyl)piperazinyl)acetonitrile (2ac): yield, 51%, (27.5 mg), light yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.45 (s, 2H), 2.60–2.43 (m, 14H), 1.55–1.47 (m, 2H), 1.34–1.18 (m, 6H), 0.82 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 114.8, 58.2, 52.5, 51.7, 45.8, 32.4, 31.4, 29.7, 29.1, 28.5, 22.5, 14.1. HRMS (ESI) m/z [M + H]+ calcd for C14H28N3S, 270.2004; found, 270.2007.
2-(4-(2-(phenylselanyl)ethyl)piperazinl)acetonitrile (2ad): yield, 80%, (49.3 mg), light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.29–7.20 (m, 3H), 3.48 (s, 2H), 3.02 (t, J = 7.2 Hz, 2H), 2.70 (t, J = 8.0 Hz, 2H), 2.63–2.49 (m, 8H). 13C NMR (101 MHz, CDCl3) δ 132.4, 130.3, 129.1, 126.9, 114.8, 58.1, 52.3, 51.7, 45.9, 24.8. HRMS (ESI) m/z [M + H]+ calcd for C14H20N3Se, 310.0817; found, 310.0819.

3.2.2. Experimental Procedures for the Synthesis of ACAT-1 Inhibitors 5a and 5b

(a)
Method 1:
Compound 2ab (60.3 mg, 0.2 mmol), KOH (44.9 mg, 0.8 mmol) and tert-butanol (2.0 mL) were mixed in a 50 mL Teflon screw-cap sealed tube. The mixture was vigorously stirred under N2 atmosphere for 1 h at 110 °C (oil bath). The reaction mixture was diluted with CH2Cl2/MeOH (10 mL, 1/1) and filtered. Solvent was removed, and the crude product was purified on a silica gel column eluted with CH2Cl2/MeOH (3:1 v/v) to afford the product 4b in 75% yield (47.9 mg). White solid. M.p. 208–209 °C. 1H NMR (400 MHz, CD3OD/CDCl3 (1:1)) δ 7.49 (dd, J = 5.8, 3.1 Hz, 2H), 7.21 (dd, J = 6.0, 3.1 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 3.07 (s, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.68 (s, 8H).
Compound 4b (6.4 mg, 0.02 mmol), 2,6-diisopropylaniline (3.5 mg, 0.02 mmol), K2S2O8 (16.2 mg, 0.06 mmol) and MeCN (3 mL) were mixed in a 50 mL Teflon screw-cap sealed tube. The mixture was vigorously stirred under N2 atmosphere for 8 h at 85 °C (oil bath). The reaction mixture was diluted with CH2Cl2/MeOH (10 mL, 1/1) and filtered. Solvent was removed, and the crude product was purified on a silica gel column eluted with CH2Cl2/MeOH (10:1 v/v) to afford product 5a as a white solid (10%, 1.0 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.13 (s, 1H), 7.40 (s, 2H), 7.24–7.19 (m, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 7.08 (dd, J = 5.9, 3.2 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), 3.11 (s, 2H), 3.04–2.93 (m, 2H), 2.68 (t, J = 6.9 Hz, 2H), 2.55 (br s, 8H), 1.08 (d, J = 6.9 Hz, 12H). 13C NMR (101 MHz, DMSO-d6) δ 169.9, 151.1, 146.4, 133.0, 128.0, 123.3, 121.8, 61. 9, 57.8, 53.6, 52.9, 29.3, 28.6, 24.0.
Compound 4b (6.4 mg, 0.02 mmol), 6-methyl-2,4-bis(methylthio)pyridin-3-amine (4.0 mg, 0.02 mmol), K2S2O8 (16.2 mg, 0.06 mmol), and MeCN (3 mL) were mixed in a 50 mL Teflon screw-cap sealed tube. The mixture was vigorously stirred under N2 atmosphere for 8 h at 85 °C (oil bath). The reaction mixture was diluted with CH2Cl2/MeOH (10 mL, 1/1) and filtered. Solvent was removed, and the crude product was purified on a silica gel column eluted with CH2Cl2/MeOH (10:1 v/v) to afford the product 5b as a white solid (12%, 1.2 mg). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.48 (dd, J = 5.4, 2.9 Hz, 2H), 7.16 (dd, J = 5.9, 3.1 Hz, 2H), 6.61 (s, 1H), 3.33–3.25 (m, 4H), 2.92–2.70 (m, 10H), 2.51 (s, 3H), 2.46 (s, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ169.2, 156.9, 156.2, 151.0, 148.4, 139.8, 122.9, 121.9, 114.2, 113.7, 61.6, 59.4, 53.5, 53.2, 29.7, 24.5, 14.0, 12.9.
(b)
Method 2:
1H-benzo[d]imidazole-2-thiol 1ab (30.0 mg, 0.2 mmol), CAABC (59.1 mg, 0.3 mmol), Cs2CO3 (195.5 mg, 0.6mmol) and EtOH (1 mL) were mixed in a 50 mL Teflon screw-cap sealed tube. The mixture was vigorously stirred under air atmosphere for 3 h at 100 °C (oil bath). The reaction mixture was diluted with CH2Cl2/MeOH (10 mL, 1/1) and filtered. Solvent was removed, and the crude product was purified on a silica gel column eluted with CH2Cl2/MeOH (6:1 v/v) to afford product 3b in 80% yield (51.9 mg). White solid. M.p. 117–118 oC. 1H NMR (400 MHz, CD3OD/CDCl3 (1:1)) δ 7.56 (d, J = 2.8 Hz, 2H), 7.31–7.25 (m, 2H), 3.51–3.45 (m, 2H), 3.21–3.18 (m, 4H), 2.95–2.89 (m, 2H), 2.84 (br s, 4H). 13C NMR (101 MHz, CD3OD/CDCl3 (1:1)) δ 154.6, 143.2, 126.1, 117.9, 62.5, 56.1, 48.5, 33.3.
A mixture of compound 3b (162.2 mg, 0.5 mmol), 2-bromo-N-(2,6-diisopropylphenyl) acetamide (149.1 mg, 0.5 mmol), and K2CO3 (414.6 mg, 3 mmol) in MeCN (10 mL) was stirred under air atmosphere for 12 h at room temperature. The reaction mixture was filtered, and solvent was removed under reduced pressure. The crude product was purified on a silica gel column eluted with CH2Cl2/MeOH (10:1 v/v) to afford compound 5a in 60% yield (143.9 mg).
A mixture of compound 3b (162.2 mg, 0.5 mmol), 2-bromo-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide (160.6 mg, 0.5 mmol) and K2CO3 (414.6 mg, 3 mmol) in MeCN (10 mL) was stirred under air atmosphere for 12 h at room temperature. The reaction mixture was filtered, and solvent was removed under reduced pressure. The crude product was purified on a silica gel column eluted with CH2Cl2/MeOH (6:1 v/v) to afford compound 5b in 75% yield (188.5 mg).

4. Conclusions

In summary, we have described a simple and eco-friendly method for the synthesis of 2-(4-(2-(phenylthio)ethyl)piperazinyl)acetonitriles (2) in one-pot. Further reactions produced aqueous soluble acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1) inhibitors such as [K-604]. The advantage of this method lies in green solvent, water and dioxygen insensitivity, less-odor disulfide source, and easy purification. Gram level of reaction with purity over 90% makes this method more practical. The methodology would prove very useful in the area of medicinal chemistry.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29163723/s1. Experimental procedures, Characterization data of products, X-ray structure determinations, Crystallographic data of compounds, and 1H NMR and 13C NMR spectra of compounds. CCDC 2328305, CCDC 2328309, CCDC 2,328,313 and CCDC 2,328,311 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 5 June 2024), or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

Author Contributions

Conceptualization, Y.H. and D.H.; methodology, Y.H.; software, Y.L.; validation, Y.H. and T.Z.; formal analysis, D.H.; investigation, T.Z.; resources, D.H.; data curation, Y.H. and D.H.; writing—original draft preparation, Y.H.; writing—review and editing, D.H.; visualization, T.Z.; supervision, D.H.; project administration, D.H.; funding acquisition, D.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (grant no. 21371171) and the Natural Science Foundation of Fujian Province (grant no. 2020J01114).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data underlying this study are available in the published article and its online Supplementary Material.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Tomass, S.I.; Pfahler, J.; Mautone, N.; Rovere, A.; Esposito, C.; Passeri, D.; Pellicciari, R.; Novellino, E.; Pannek, M.; Steegborn, C.; et al. Synthesis and Evaluation of Cyclic Secondary Amine Substituted Phenyl and Benzyl Ni-trofuranyl Amides as Novel Antituberculosis Agents. ACS Med. Chem. Lett. 2020, 11, 862–868. [Google Scholar]
  2. Geng, F.; Cheng, X.; Wu, X.; Yoo, J.Y.; Cheng, C.; Guo, J.Y.; Mo, X.; Ru, P.; Hurwitz, B.; Kim, S.-H.; et al. Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1-Mediated Lipogenesis. Clin. Cancer Res. 2016, 22, 5337–5348. [Google Scholar] [CrossRef] [PubMed]
  3. Ohmoto, T.; Nishitsuji, K.; Yoshitani, N.; Mizuguchi, M.; Yanagisawa, Y.; Saito, H.; Sakashita, N. K604, a Specific Acyl-CoA: Cholesterol Acyltrans-ferase 1 Inhibitor, Suppresses Proliferation of U251-MG Glio-blastoma Cells. Mol. Med. Rep. 2015, 12, 6037–6042. [Google Scholar] [CrossRef] [PubMed]
  4. Yang, W.; Bai, Y.; Xiong, Y.; Zhang, J.; Chen, S.; Zheng, X.; Meng, X.; Li, L.; Wang, J.; Xu, C.; et al. Potentiating the Antitumour Response of CD8+T Cells by Modulating Cholesterol Metabolism. Nature 2016, 531, 651–655. [Google Scholar] [CrossRef] [PubMed]
  5. Ballet, S.; Mauborgne, A.; Bourgoin, S.; Caussade, F.; Cloarec, A.; Hamon, M.; Cesselin, F.; Collin, E. Effects of the Analgesic Drug up 26-91 on the in vivo Release of Substance P and Cal-citonin Gene-Related Peptide from the Rat Spinal Cord. Fundam. Clin. Pharmacol. 1997, 11, 151–199. [Google Scholar]
  6. Corsano, S.; Strappaghetti, G.; Codagnone, A.; Scapicchi, R.; Marucci, G. Synthesis and Pharmacological Activity of Some New Pyridazinones. Eur. J. Med. Chem. 1992, 21, 545–549. [Google Scholar] [CrossRef]
  7. Qian, H.; Zhao, X.; Yan, R.; Yao, X.; Gao, S.; Sun, X.; Du, X.; Yang, H.; Wong, C.C.L.; Yan, N. Structural Basis for Catalysis and Substrate Specificity of Human ACAT1. Nature 2020, 581, 333–338. [Google Scholar] [CrossRef] [PubMed]
  8. Shibuya, K.; Kawamine, K.; Ozaki, C.; Ohgiya, T.; Edano, T.; Yoshinaka, Y.; Tsunenari, Y. Discovery of Clinical Candidate 2-(4-(2-((1H-Benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide Hydrochloride [K-604], an Aqueous-Soluble Acyl-CoA: Cho-lesterol O-Acyltransferase-1 Inhibitor. J. Med. Chem. 2018, 61, 10635–10650. [Google Scholar] [CrossRef] [PubMed]
  9. Chang, T.-Y.; Chang, C.C.Y.; Bryleva, E.; Rogers, M.A.; Murphy, S.R. Neuronal Cholesterol Esterification by ACAT1 in Alzheimer’s Disease. IUBMB Life 2010, 62, 261–267. [Google Scholar] [CrossRef]
  10. Shibuya, Y.; Chang, C.C.Y.; Huang, L.-H.; Bryleva, E.Y.; Chang, T.-Y. Inhibiting ACAT1/SOAT1 in Microglia Stimulates Au-tophagy-Mediated Lysosomal Proteolysis and Increases A1-42 Clearance. J. Neurosci. 2014, 34, 14484–14501. [Google Scholar] [CrossRef]
  11. Yamanaka, K.; Urano, Y.; Takabe, W.; Saito, Y.; Noguchi, N. Induction of Apoptosis and Necroptosis by 24(S)-Hydroxycholesterol is Dependent on Activity of Acyl-CoA: Cholesterol Acyltrans-ferase 1. Cell Death Dis. 2014, 5, e990. [Google Scholar] [CrossRef] [PubMed]
  12. Shibuya, Y.; Chang, C.C.Y.; Chang, T.-Y. ACAT1/SOAT1 as a Therapeutic Target for Alzheimer’s Disease. Future Med. Chem. 2015, 7, 2451–2467. [Google Scholar] [CrossRef]
  13. Shibuya, K.; Watanabe, T.; Urano, Y.; Takabe, W.; Noguchi, N.; Kitagishi, H. Synthesis of 24(S)-Hydroxycholesterol Esters Responsible for the Induction of Neuronal Cell Death. Bioorg. Med. Chem. 2016, 24, 2559–2566. [Google Scholar] [CrossRef]
  14. Takabe, W.; Urano, Y.; Vo, D.-K.H.; Shibuya, K.; Tanno, M.; Kitagishi, H.; Fujimoto, T. Esterification of 24(S)-Hydroxycholesterol Induces Formation of Atypical Lipid Droplet-Likestructures, Leading to Neuronal Cell Death. J. Lipid Res. 2016, 57, 2005–2014. [Google Scholar] [CrossRef] [PubMed]
  15. Li, J.; Gu, D.; Lee, S.S.-Y.; Song, B.; Bandyopadhyay, S.; Chen, S.; Konieczny, S.F.; Ratliff, T.L.; Liu, X.; Xie, J.; et al. Abrogating Cholesterol Esterification Suppresses Growth and Metastasis of Pancreatic Cancer. Oncogene 2016, 35, 6378–6388. [Google Scholar] [CrossRef] [PubMed]
  16. Saraon, P.; Trudel, D.; Kron, K.; Dmitromano-lakis, A.; Trachtenberg, J.; Bapat, B.; Kwast, T.V.D.; Jarvi, K.A.; Diamandis, E.P. Evaluation and Prognostic Significance of ACAT1as a Marker of Prostate Cancer Progression. Prostate 2014, 74, 372–380. [Google Scholar] [CrossRef]
  17. Mulas, M.F.; Abete, C.; Pulisci, D.; Pani, A.; Massidda, B.; Dess, D.; Mandas, A. Cholesterol Esters as Growth Regulators of Lymphocytic Leukaemia Cells. Cell Prolif. 2011, 44, 360–371. [Google Scholar] [CrossRef]
  18. Stevenson, E.R.; Wilkinson, M.L.; Abramova, E.; Guo, C.J.; Gow, A.J. Intratracheal Administration of Acyl Coenzyme a Acyltransferase-1 Inhibitor K-604 Reduces Pulmonary Inflammation following Bleomycin-Induced Lung Injury. J. Pharmacol. Exp. Ther. 2020, 382, 356–365. [Google Scholar] [CrossRef]
  19. Siracusa, M.A.; Salerno, L.; Modica, M.N.; Pittala, V.; Romeo, G.; Amato, M.E.; Nowak, M.; Bojarski, A.J.; Mereghetti, I.; Cagnotto, A.; et al. Synthesis of New Arylpiperazinylalkylthiobenzimidazole, Benzothiazole, or Benzoxazole Derivatives as Potent and Selective 5-HT1A Serotonin Receptor Ligands. J. Med. Chem. 2008, 51, 4529–4538. [Google Scholar] [CrossRef]
  20. Shibuya, K.; Miura, T.; Ohgiya, T.; Omichi, K.; Tsunenari, Y. Syntheses and Pharmacokinetic Evaluations of Four Metabolites of 2-(4-(2-((1H-benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis-(methylthio)pyridin-3-yl)acetamide Hydro-chloride [K-604], an AcylCoA: Cholesterol O-acyltransferase-1 Inhibitor. Bioorg. Med. Chem. 2020, 28, 115457. [Google Scholar]
  21. Maffuid, K.A.; Koyioni, M.; Torrice, C.D.; Murphy, W.A.; Mewada, H.K.; Koutentis, P.A.; Crona, D.J.; Asquith, C.R.M. Design and Evaluation of 1,2,3-Dithiazoles and Fused 1,2,4-Dithiazines as Anti-Cancer Agents. Bioorg. Med. Chem. Lett. 2021, 43, 128078. [Google Scholar] [CrossRef] [PubMed]
  22. Linciano, P.; Sorbi, C.; Rossino, G.; Rossi, D.; Marsala, A.; Denora, N.; Bedeschi, M.; Marino, N.; Miserocchi, G.; Dondio, G.; et al. Novel S1R Agonists Counteracting NMDA Excitotoxicity and Oxidative Stress: A Step forward in the Discovery of Neuroprotective Agents. Eur. J. Med. Chem. 2023, 249, 115163. [Google Scholar] [CrossRef] [PubMed]
  23. Zhu, Q.; Yuan, Q.; Chen, M.; Guo, M.; Huang, H. Multicomponent Reactions with Cyclic Tertiary Amines Enabled by Facile C-N Bond Cleavage. Angew. Chem. Int. Ed. 2017, 56, 5101–5105. [Google Scholar] [CrossRef] [PubMed]
  24. Bugaenko, D.I.; Yurovskaya, M.A.; Karchava, A.V. Qua-ternary N-(2-Pyridyl)-DABCO Salts: One-Pot in Situ For-mation from Pyridine-N-oxides and Reactions with Nucleo-philes: A Mild and Selective Route to Substituted N-(2-Pyridyl)-N′-ethylpiperazines. J. Org. Chem. 2017, 82, 2136–2149. [Google Scholar] [CrossRef] [PubMed]
  25. Min, G.; Seo, J.; Ko, H.M. Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process. J. Org. Chem. 2018, 83, 8417–8425. [Google Scholar] [CrossRef] [PubMed]
  26. Maras, N.; Polanc, S.; Kocevar, M. Ring-Opening Reactions of 1,4-Diazabicyclo[2.2.2]octane (DABCO) Derived Quater-nary Ammonium Salts with Phenols and Related Nucleophiles. Org. Biomol. Chem. 2012, 10, 1300–1310. [Google Scholar] [CrossRef] [PubMed]
  27. Bugaenko, D.I.; Yurovskaya, M.A.; Karchava, A.V. N-Arylation of DABCO with Diaryliodonium Salts: General Synthesis of N-Aryl-DABCO Salts as Precursors for 1,4-Disubstituted Piperazines. Org. Lett. 2018, 20, 6389–6393. [Google Scholar] [CrossRef] [PubMed]
  28. Asar, F.J.; Soleymani, F.; Hooshmand, S.E.; Halimehjani, A.Z. Direct Synthesis of Piperazines Containing Dithiocarbamate Derivatives via DABCO Bond Cleavage. Tetrahedron Lett. 2020, 61, 152610. [Google Scholar] [CrossRef]
  29. Hajizadeh, F.; Mojtahedi, M.M.; Abaee, M.S. One-Pot Four-Component Synthesis of Novelisothiourea-Ethylene-Tethered-Piperazinederivatives. RSC Adv. 2023, 13, 32772–32777. [Google Scholar] [CrossRef]
  30. Shibuya, K.; Kawamine, K.; Sato, Y.; Miura, T.; Ozaki, C.; Edano, T.; Hirata, M. Novel Cyclic Diamine Compounds and Medicine Containing the Same. U.S. Patent 6,969,711, 29 November 2011. [Google Scholar]
  31. Shibuya, K.; Ohgiya, T.; Sato, Y.; Miura, T. Processes for Production of Cyclic Diamine Compounds or Salts Thereof. U.S. Patent 6,998,486, 14 February 2006. [Google Scholar]
  32. Shibuya, K.; Tosaka, A. Method for Producing Cyclic Diamine Derivative. U.S. Patent 7,576,203, 18 September 2009. [Google Scholar]
Molecules 29 03723 sch001
Scheme 1. Different strategies (a) [8,19,20,21,22], (b) [23,24,25], and (c) [26,27,28,29] to synthesize sulfur-containing ethyl piperazine compounds.
Scheme 1. Different strategies (a) [8,19,20,21,22], (b) [23,24,25], and (c) [26,27,28,29] to synthesize sulfur-containing ethyl piperazine compounds.
Molecules 29 03723 sch001
Molecules 29 03723 sch002
Scheme 2. Different strategies (route 1 [8]; route 2 [20,30,31,32]) to synthesize the ACAT-1 inhibitor [K-604].
Scheme 2. Different strategies (route 1 [8]; route 2 [20,30,31,32]) to synthesize the ACAT-1 inhibitor [K-604].
Molecules 29 03723 sch002
Molecules 29 03723 g002
Figure 2. Scope of disulfides with respect to compounds 2 a,b; a Reaction conditions: 1 (0.1 mmol), CAABC (0.2 mmol), TMSCN (0.22 mmol), Cs2CO3 (0.6 mmol), EtOH (1 mL), air, 100 °C, 3 h, isolated yields. b Reactions were conducted using 2-mercaptobenzoxazole (0.2 mmol) and 2-mercapto benzimidazole (0.2 mmol) as substrates.
Figure 2. Scope of disulfides with respect to compounds 2 a,b; a Reaction conditions: 1 (0.1 mmol), CAABC (0.2 mmol), TMSCN (0.22 mmol), Cs2CO3 (0.6 mmol), EtOH (1 mL), air, 100 °C, 3 h, isolated yields. b Reactions were conducted using 2-mercaptobenzoxazole (0.2 mmol) and 2-mercapto benzimidazole (0.2 mmol) as substrates.
Molecules 29 03723 g002
Molecules 29 03723 sch003
Scheme 3. Control experiments: (a) Study the influence of O2 on the yield; (b) Examine the reaction using thiophene as the thiolate source; (c) Examine the reaction in the absence of TMSCN; (d) Examine the reaction by the replacement of CAABC with CYAABC; (e) Examine the reaction by the replacement of CAABC with DABCO; (f) Examine the reaction by the replacement of CAABC with EAABB; (g) Check the standard reaction without the presence of PhSSPh.
Scheme 3. Control experiments: (a) Study the influence of O2 on the yield; (b) Examine the reaction using thiophene as the thiolate source; (c) Examine the reaction in the absence of TMSCN; (d) Examine the reaction by the replacement of CAABC with CYAABC; (e) Examine the reaction by the replacement of CAABC with DABCO; (f) Examine the reaction by the replacement of CAABC with EAABB; (g) Check the standard reaction without the presence of PhSSPh.
Molecules 29 03723 sch003
Molecules 29 03723 sch004
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 29 03723 sch004
Molecules 29 03723 sch005
Scheme 5. Exploration of the synthesis of ACAT-1 inhibitors 5a and 5b: (a) Our method 1 to prepare [K-604]; (b) Our method 2 to prepare [K-604].
Scheme 5. Exploration of the synthesis of ACAT-1 inhibitors 5a and 5b: (a) Our method 1 to prepare [K-604]; (b) Our method 2 to prepare [K-604].
Molecules 29 03723 sch005
Molecules 29 03723 g003
Figure 3. Crystal structures of compounds 2b (CCDC 2328305), 2ab (CCDC 2328309), 3b (CCDC 2328313), 4b (CCDC 2328311) and 5a showing thermal ellipsoids of 50% probability surfaces. The structure of 5a was solved by fast-data collection with the crystallographic data shown in Supplementary Materials.
Figure 3. Crystal structures of compounds 2b (CCDC 2328305), 2ab (CCDC 2328309), 3b (CCDC 2328313), 4b (CCDC 2328311) and 5a showing thermal ellipsoids of 50% probability surfaces. The structure of 5a was solved by fast-data collection with the crystallographic data shown in Supplementary Materials.
Molecules 29 03723 g003
Table 1. Optimization of the formation of compound 2a a.
Table 1. Optimization of the formation of compound 2a a.
Molecules 29 03723 i001
EnBaseSolventTemp/°CTime/hYield b
1Cs2CO3EtOH100390%
2K2CO3EtOH100373%
3Na2CO3EtOH100357%
4KOHEtOH100335%
5tBuOKEtOH100330%
6Cs2CO3EtOH/H2O (7:3)100355%
7Cs2CO3H2O1003trace
8Cs2CO3MeOH100375%
9Cs2CO3DMF1003none
10Cs2CO3DMSO1003none
11Cs2CO3EtOH120388%
12Cs2CO3EtOH80382%
13Cs2CO3EtOH100687%
14Cs2CO3EtOH100172%
a Reaction conditions: 1a (0.1 mmol), 1-(chloromethyl)-4-aza-1-azoniabicyclo[2.2.2]octane chloride (0.2 mmol), TMSCN (0.22 mmol), base (0.6 mmol), solvent (1 mL), air atmosphere. b Yields were determined by 1H NMR analysis of the crude product using 1,3,5-trimethoxybenzene as the internal standard; Temp = temperature; En = entry.
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Huang, Y.; Zhu, T.; Li, Y.; Huang, D. Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors. Molecules 2024, 29, 3723. https://doi.org/10.3390/molecules29163723

AMA Style

Huang Y, Zhu T, Li Y, Huang D. Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors. Molecules. 2024; 29(16):3723. https://doi.org/10.3390/molecules29163723

Chicago/Turabian Style

Huang, Ying, Tingyu Zhu, Yinghua Li, and Deguang Huang. 2024. "Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors" Molecules 29, no. 16: 3723. https://doi.org/10.3390/molecules29163723

APA Style

Huang, Y., Zhu, T., Li, Y., & Huang, D. (2024). Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors. Molecules, 29(16), 3723. https://doi.org/10.3390/molecules29163723

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