A Convenient One-Pot Preparation of 2-Methyl-3-(phenylthio- methyl)quinolines from Morita-Baylis-Hillman Adducts and Their Oxidation to the Corresponding Sulfones

A convenient one-pot preparation of 2-methyl-3-(phenylthiomethyl)quinolines from Morita-Baylis-Hillman adducts via conjugate addition of thiols followed by reductive cyclization with Fe/AcOH was developed. The 2-methyl-3-(phenylthiomethyl)quinolines were transformed into 2-methyl-3-(phenylsulfonylmethyl)quinolines via m-CPBA-mediated oxidation.


Introduction
The quinoline nucleus is a ubiquitous heterocyclic structural motif that is found in many naturally occurring quinoline alkaloids, therapeutic and synthetic compounds with a wide spectrum of biological activities such as antimalarial, antidiabetic, anti-inflammatory, antiasthmatic, antihypertensive, antibacterial, tyrosine kinase inhibiting agents [1][2][3][4]. Quinoline and their derivatives have been utilized for the construction of nano-and meso structures having enhanced electronic and photonic properties [5]. In particular, the C3-alkylsulfone-containing quinolines posess important biological activities. Some of the important C3-alkylsulfonyl and C3-alkylsulfoxide quinoline derivatives are depicted in Figure 1 [6,7]. Compound A displayed excellent functional activity, compound B exhibits excellent in vivo/in vitro DMPK profile and acts as potent NK3 receptor antagonists [6]. Similarly, compound C acts as

Results and Discussion
Recently, we developed an easily accessible method for the synthesis of indolylquinoline derivatives from MBH adducts [26]. Taking cues from this reaction, we envisioned synthesizing C3-arylthiomethylquinoline derivatives from MBH adducts derived from the reaction of 2-nitrobenzaldehydes and methyl vinyl ketone. Our synthetic strategy for accessing 2-methyl-3-(phenylsulfonylmethyl)quinoline derivatives is outlined in Scheme 1. The starting MBH adducts were prepared according to a previously reported procedure [31]. Initially, the MBH adduct 1a was treated with benzenethiol 2a in the presence of triethylamine in THF at room temperature to yield intermediate compound 3a, which was treated with Fe/AcOH heated under reflux conditions to give the corresponding 2-methyl-3-(phenylthiomethyl)quinoline compound 4a. Subsequently, sulfide 4a was subjected to oxidation with a stoichiometric amount of 3-chloroperoxybenzoic acid (m-CPBA) and sodium permanganate in 1,4-dioxane/water (1:1) at room temperature for 20 min, to provide the expected the 2-methyl-3-(phenylsulfonylmethyl)quinoline compound 5a. The first two steps of Scheme 1 were conducted in a one-pot operation. Scheme 1. Outline of our synthetic route for the synthesis of 2-methyl-3-(phenylthiomethyl) quinoline derivatives and 2-methyl-3-(phenylsulfonylmethyl)quinoline derivatives. R  A literature survey revealed that the addition of thiols to MBH acetates takes place either at the γ-position via a S N 2' reaction [22][23][24][25] or mixture of the products [major product at γ-position (E/Z = 10:1) and trace amount of product at α-position] [25]. In order to determine the structure of the intermediates 3a-3r in our process, we conducted the reaction of MBH adduct 1a with naphthalene thiol 2h in the presence of triethylamine. The intermediate 3h obtained from this reaction was isolated and analysed by the 1 H-and 13 C-NMR, which revealed that the intermediate 3h formed is 4-hydroxy-3-((naphthalen-1-ylthio)methyl)-4-(2-nitrophenyl)butan-2-one and it is obtained as mixture of diastereomers. When it was subjected to crystallization, the major diastereomer (with the relative configuration 7S* and 8S*) was crystallized out. The structure of the major diastereomer was confirmed by single crystal X-ray diffraction analysis ( Figure 2).  Hence it is quite clear that the intermediate 3h obtained from the reaction of MBH alcohol and thiol is a conjugate adduct, which is different from the product from the reaction of MBH acetate and thiol [22][23][24][25]. However, our main aim was the synthesis of 2-methyl-3-(phenylthiomethyl)quinoline derivatives 4a-r in a one-pot operation, therefore without further isolation of other intermediates 3a-r (tetrahydrofuran solvent was simply removed under reduced pressure) we carried out the next step to obtain the 2-methyl-3-(phenylthiomethyl)quinoline derivatives 4a-r.
The results presented in Table 1 reveal that thiophenol, thionaphthol and thiophenols containing alkyl, methoxy and halo substituents in the phenyl ring smoothly furnished the corresponding alkyl and arylthiomethylquinolines 4a-r in 64-75% yields. There was no significant effect of the nature of the substituents on the yields of the products. All the products were fully characterized by 1 H-and 13 C-NMR as well as LR and HRMS. A plausible mechanism for the formation of the 2-methyl-3-(phenylthiomethyl)quinoline derivatives from the corresponding MBH adducts via reductive cyclization in the presence of Fe/AcOH is presented in Scheme 2.

Scheme 2.
A Plausible mechanism for the formation of 2-methyl-3-(phenylthiomethyl) quinoline derivatives. Owing to the well known bioactivity of sulfones [33], the derived alkyl and arylthiomethylquinolines 4a-k were oxidized to the corresponding sulfones 5a-k in 75-89% yields (Table 2), following a reported procedure [34]. Here too, the substituents didn't have any significant effect on the yields of the products. As before, all these products were also fully characterized by 1 H-and 13 C-NMR and by LR and HRMS data.

General
All the reactions were performed in oven (130 °C) dried glassware under an inert atmosphere of nitrogen unless otherwise specified. Solvents for extraction and chromatography were distilled before use. All the chemicals used in this study were of commercial grade and used after distillation. Analytical thin layer chromatography was performed with E. Merck silica gel 60 F254 aluminum plates. All purifications were carried out by flash chromatography using 230-400 mesh silica gel. 1 H and 13 C-NMR were recorded on a Bruker Avance EX 400 FT NMR (Taipei, Taiwan). Chemical shifts were reported in parts per million (δ) using TMS as internal standard and coupling constants were expressed in Hertz. Mass spectra were obtained on a JOEL SX-102A spectrometer (Taipei, Taiwan) at an ionization potential of 70 eV and data are reported as mass/charge (m/z) with the percent relative abundance. High-resolution mass spectra (HRMS) were acquired with a Finnigan MAT-95XL spectrometer (Taipei, Taiwan).

General Procedure for the Synthesis of Compounds 4a-r
To a stirred solution of MBH adduct 1a (3.0 mmol, 1 equiv) and benzenethiol 2a (1.2 equiv) in THF (15 mL), triethylamine (1.5 equiv) was added dropwise, and the reaction mixture was allowed to continue at room temperature for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure. The residue was diluted with AcOH (15 mL) and Fe powder (6.0 equiv) at room temperature was added. Then the reaction mixture was heated at 110 °C for 2 h and was cooled to room temperature. AcOH was removed under reduced pressure and the residue was diluted with EtOAc (30 mL). The resulting mixture was filtered to remove any iron impurities. Iron residue was washed twice with EtOAc (30 mL). Filtrate and washings were combined and dried over anhydrous Na 2 SO 4 . Solvent was evaporated and the residue, thus obtained was purified by column chromatography to provide the desired product 4a as yellow solid in 66% isolated yield.

General Procedure for the Synthesis of Compounds 5a-k
To a stirred solution of sulfide 4a (2.0 mmol, 1 equiv) in 1:1 1,4-dioxane/H 2 O (12 mL) was added m-CPBA (2.0 equiv.) followed by sodium permanganate (2.0 equiv.) at room temperature (25 °C), and the reaction mixture was stirred at same temperature for 20 min. After completion of the reaction as monitored by TLC, the reaction mixture was extracted with EtOAc (30 mL), then organic layer was washed with saturated NaHCO 3 , water, followed by brine solution and dried over Na 2 SO 4 . Solvent was evaporated and obtained crude product was purified by column chromatography to provide the desired sulfone 5a as yellow solid in 85 % isolated yield.