Creation of 4-Quinolone Thioether and Selenoether Derivatives via Pd-NHC Catalysed Cross-Coupling Reaction

Abstract

Pd-NHC catalysed direct sulfenylation and selenylation of 3-iodo-4-quinolones has been developed. This protocol provides an alternative route for the construction of ipso-C–S and C–Se bond formation in 4-quinolones under aerobic conditions.

Key words

4-quinolone - Pd-NHC - sulfenylation - selenylation - cross-coupling

Thioether-functionalised heterocycles are an important class of compounds that are widely found in organic dyes, pharmaceuticals, functional materials, agrochemicals, bioactive products and drugs.[1] As a result, various methods are available for C–S cross-coupling reactions since its first report by Migita et al. in 1978.[2] A variety of thioethers have been found to have applications in the treatment of various diseases such as Parkinson’s,[3] Alzheimer’s,[4] HIV,[5] and breast cancer.[6] Similarly, organoselenium compounds have been shown to demonstrate anticancer, antiviral, antitumor, antimicrobial and antioxidant activities.[7] On account of their hydrogen-bond acceptor and electron-donor properties, organoselenium compounds can dramatically enhance the biological­ activity of the parent structure.[8] An example is Ebselen, an organoselenium compound introduced in 1980 as a neuroprotective and antioxidant agent.[9] Structures of representative biologically active moieties containing diaryl sulfide and selenide moieties are shown in Figure [1]. In view of their importance in the field of biology, the development of highly efficient and simple protocols for construction of C–S and C–Se linkages continues to be of interest.[10]

Figure 1 Representative examples of important biologically active scaffolds containing C–S and C–Se linkages

4-Quinolones frequently feature in pharmaceutical chemistry exhibiting properties such as antibacterial,[11] antimalarial,[12] and anticancer activities.[13] As a consequence, the synthesis of 4-quinolones and their derivatives has received considerable interest and various synthetic procedures are available in the literature.[14] 3-Aryl- or 3-heteroaryl-substituted quinolones have been widely explored because of their profound biological activities.[15] However, functionalisation at C-3 of quinolin-4-ones remains a challenging task due to the requirement for NH prefunctionalisation and protection. Recently, Zhang et al. introduced a technique for thioetherification at C-3 of 4-quinolones via Pd catalysed decarboxylation.[16] However, this protocol has some limitations including harsh reaction conditions, extended reaction times, requiring halogen-substituted 4-quinolone substrates and prerequisite NH protection.

Scheme 1 Previous methodologies for the synthesis of thioether derivatives of 4-quinolone. An approach for the synthesis of C–S and C–Se cross-coupled product is reported herein.

Table 1 Pd-NHC Catalysed C–S Cross Coupling: Effect of Reaction Parameters^­a

Entry	Catalyst (mol%)	Base	Solvent	Temp (°C)	Time (h)	Yield (%)b
1	Pd(OAc)2 (5)	DBU	DMF	80	4	80
2	Pd(OAc)2 (5)	K2CO3	DMF	80	4	71
3	PdCl2 (5)	K2CO3	DMF	80	4	73
4	Pd(acac)2 (5)	K2CO3	DMF	80	4	70
5	Pd(PPh3)4 (5)	K2CO3	DMF	80	4	53
6	Pd-NHC (2)	K2CO3	DMF	80	2	75
7	Pd-NHC (1)	DBU	DMF	80	2	83
8	Pd-NHC (1)	Et3N	DMF	80	2	79
9	Pd-NHC (1)	Cs2CO3	DMF	80	2	52
10	Pd-NHC (1)	DBU	1,4-dioxane	80	2	70
11	Pd-NHC (1)	DBU	DMF	40	2	67
12	Pd-NHC (1)	DBU	DMF	rt	2	59
13	Pd-NHC (0.5)	K2CO3	DMF	80	2	72
14	Pd-NHC (0.5)	DBU	DMF	80	2	86

^a Reaction conditions: 3-iodo-2-phenyl substituted 4-quinolone (0.25 mmol, 86 mg), thiophenol (1.5 equiv, 0.375 mmol, 41 mg), base (0.5 mmol).

^b Isolated yield after purification by column chromatography.

In this area, we have previously reported the regiocontrolled nitration at C-5 and C-7 of 4-quinolones under ambient conditions,[17a] regioselective bromination at C-6 and subsequent arylation via Suzuki cross coupling,[17b] synthesis of 3-aroyl-quinolin-4(1H)-ones from 3-iodo-quinolin-4(1H)-ones using carbonylative Suzuki coupling,[17c] carbonylative Sonogashira annulation for the formation of 2-substituted 4-quinolone derivatives,[17d] synthesis of N-arylated derivatives under ligand free and ambient conditions,[17e] and NaI-mediated, metal-free synthesis of thioether and selenoether derivatives.[17f] More recently, we have disclosed a transition-metal free approach for the regioselective C-3 thiocyanation and selenocyanation of the 4-quinolone scaffold.[17g] Herein, we disclose a novel, simple and efficient route for Pd-NHC[18] catalysed thioetherification and selenylation of 3-iodo-4-quinolones in good yields under aerobic conditions (Scheme [1]). To our knowledge, no such study has been documented before.

Our initial study began with the reaction between 3-iodo-2-phenyl-4-quinolone (1a) and thiophenol. After a reaction mixture containing 5 mol% Pd(OAc)₂ and 2 equiv of DBU in DMF was heated at 80 °C for 4 h, compound 2a was isolated in 80% yield (Table [1], entry 1). Under identical conditions, when switching to an inorganic base (K₂CO₃) the yield of product 2a decreased to 71%. In the presence of K₂CO₃­, commercially available Pd salts such as Pd(OAc)₂, PdCl₂­, and Pd(acac)₂ resulted in similar yields of the cross-coupled product (entries 2–4). Furthermore the yield of the anticipated thioether derivative decreased when Pd(PPh₃)₄ was used as catalyst (entry 5). It was found that in the presence of just 2 mol% of Pd-NHC catalyst the reaction was complete within 2 h, resulting in the desired cross-coupled product in 75% yield (entry 6). From the optimization table, it is evident that organic bases are more effective. When the cross-coupling reaction was carried out in the presence of 1 mol% Pd-NHC catalyst, after 2 h, 83% of the cross-coupled product was isolated when DBU was used as base (entry 7). An similar yield of product was observed using Et₃N as base but upon using Cs₂CO₃ as base the yield dropped to 52% (entry 9). Furthermore, we found a direct relationship between yield of cross-coupled product and the reaction temperature. Carrying out the reaction at lower temperatures resulted in lower yields (entries 11, 12). After screening the different parameters, we found the combination of Pd-NHC as catalyst, DBU as base and DMF as solvent was optimal. Notably, 0.5 mol% of Pd-NHC as catalyst afforded 2a in 86% yield within 2 h at 80 °C and served as optimal conditions for this protocol (entry 14).

With the optimised reaction conditions in hand, we explored the substrate scope of both 3-iodo-substituted 4-quinolones and variously substituted thiols (Scheme [2]). A broad range of thiophenols were reacted with various 3-iodo-2-phenylquinolin-4-(1H)ones, affording the corresponding 3-aryl sulfide-4-quinolones in good to excellent yields. Both thiophenols possessing electron-donating and electron-withdrawing groups performed well in this transformation. 4-Fluorothiophenol coupled with 3-iodo-2-phenylquinolin-4-(1H)one, resulting in 88% yield of the desired product 2e. Likewise, 2-thionaphthol furnished moderate to excellent yields (73–86%; 2g, 2k, 2r). The greater steric bulk of the naphthyl might play a role in lowering the yield of 2g and 2r. Next, we examined the influence of various groups at C-2 of the 4-quinolone substrate. It was found that electron-withdrawing groups at C-2 afforded much higher yields in comparison to electron-donating substituents (2h–l, 2m, 2n, 2q, 2r). 2-Cyclohexyl-4-quinolone also proved to be a good coupling partner with 4-chlorothiophenol (2n). The highest yield was obtained when 2-(4-fluorophenyl)-3-iodo-4-quinolone was coupled with 4-fluorothiophenol to give 2j. Surprisingly, 2-(2-methylphenyl)-3-iodo-4-quinolone did not afford the corresponding product 2s. The reaction was complete in 1–2 h. Cyclohexanethiol smoothly participated in this sulfenylation reaction and furnished the desired product 2t in 58% yield.

Scheme 2 Substrate scope for the Pd-NHC catalysed thioetherification. Reagents and conditions: 3-iodo-2 substituted-4-quinolone (0.25 mmol), thiophenol (0.375 mmol), DBU (0.5 mmol, 76 mg), DMF (2 mL) at 80 °C. Isolated yield after column chromatography. ^a Using PhSSPh (1.5 equiv).

Once the synthesis of various thioethers had been explored, we extend the protocol to the corresponding C–Se cross-coupling between various 3-iodo-2-phenyl-4-quinolones and diphenyl diselenide. Gratifyingly, the methodology proved to be general and we obtained the corresponding products 3a–g in good to excellent yields (Scheme [3]). It is important to note that electronic effects of the 2-substituents on the 4-quinolone have a profound impact on the yield of selenide derivatives. 4-Quinolones possessing 2-cyclohexyl and 2-cyclopropyl substituents gave the highest yields of the corresponding products 3b and 3f, whereas 2-aryl substituents possessing electron-withdrawing group such as 4-chloro and 4-fluoro resulted in comparatively low yields of the coupled products 3c and 3d. The lowest yield was observed for 2-(4-cyanophenyl)-4-quinolone, which furnished only 48% of the desired coupling product 3e.

Scheme 3 Substrate scope of the Pd-NHC catalysed selenylation. Reagents and conditions: 3-iodo-2-substituted- 4-quinolone (0.25 mmol), diphenyl diselenide (0.375 mmol), DBU (0.5 mmol, 76 mg), DMF (2 mL) at 80 °C. Isolated yield after purification by column chromatography.

The catalytic cycle for the C–S and C–Se cross-coupling reactions of 4-quinolone derivatives initiated from in situ generation of Pd(0) species follows the standard pathway and is shown in Scheme [4]. Oxidative addition to the 3-iodo-2-substituted-4-quinolone affords aryl palladium intermediate A. Next, transmetallation of the thiophenol or organodiselenide with aryl palladium complex A forms intermediate B and the desired 3-sulfenylated or 3-selenylated derivative is obtained after reductive elimination with concomitant regeneration of the Pd(0) species, which enters the next catalytic cycle.

Scheme 4 Plausible mechanism of the Pd-NHC catalysed C–S/C–Se cross-coupling of 4-quinolone

In summary, we have revealed an alternative method for the synthesis of ipso-C–S and C–Se substituted 4-quinolone derivatives through Pd-NHC catalysed cross-coupling reaction.[19] This method should be attractive to the synthetic and pharmaceutical chemistry community for the library synthesis of 4-quinolone derivatives. Biological screenings of all compounds synthesised herein are under investigation in our laboratory.

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• 19 2-Phenyl-3-(phenylthio)quinolin-4(1H)-one (2a); Typical Procedure: 3-Iodo-2-phenyl-substituted 4-quinolone (0.25 mmol), thiophenol (0.375 mmol), DBU (0.5 mmol, 76 mg) and Pd-NHC (0.5 mol%, 1.2 mg) were dissolved in DMF (2 mL) in a 25 mL round-bottomed flask and the mixture was heated to 80 °C for 1–2 h. The mixture was then cooled, diluted with water, and the product was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was then purified by column chromatography, eluting with petroleum ether/ethyl acetate to give the product as a white solid (mp 191–193 °C). ¹H NMR (300 MHz, DMSO-d ₆): δ = 12.29 (s, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.71–7.73 (m, 2 H), 7.48–7.54 (m, 5 H), 7.41 (s, 1 H), 7.14–7.20 (m, 2 H), 6.97–7.05 (m, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 175.5, 139.9, 138.8, 135.5, 132.8, 130.2, 129.1, 129.0, 128.5, 125.9, 125.5, 124.8, 124.7, 124.5, 119.2, 108.5. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₁H₁₆NOS: 330.0952; found: 330.0972.