Synthesis of New Water-Soluble Bunte Salts Bearing Thieno[2,3-b]Pyridine-3-yl Substituents ^†

Abstract

Upon treatment with chloroacetyl chloride, 3-aminothieno[2,3-b]pyridines gave the corresponding chloroacetamides. The latter readily react with sodium thiosulphate to afford water soluble S-alkylthiosulphates with pharmacophoric heterocyclic units.

1. Introduction

Bunte salts (Figure 1) are easily available and handy reagents that are useful for the introduction of sulfur-containing fragments into a molecule [1]. They are practically odorless crystalline solids that appear to be water soluble even if they contain highly lipophilic organic fragments [1]. Bunte salts are useful in organic synthesis as “surrogates of sulfur” [2,3,4], in the synthesis of metal nanoparticles [5,6,7,8,9] and as complexing agents. In addition, some of these compounds reveal interesting biological activity [10]. It is known that Bunte salts are stable in aqueous media, whereas the corresponding alkylthiosulfuric acids, RSSO₃H, are usually unstable in aqueous solution [11]. A survey of the literature revealed a couple of methods to prepare Bunte salts [12,13]. The most common approach is based on the reaction of alkyl halides with readily available and cheap sodium thiosulfate [13]. Here, we propose a new approach to the synthesis of Bunte salts bearing a pharmacophoric aminothieno[2,3-b]pyridine (Figure 1) core. 3-Aminothieno[2,3-b]pyridines are known to exhibit a broad spectrum of biological activity and they have been recognized as valuable reagents for heterocyclic synthesis [14,15,16,17].

2. Results and Discussion

3-Aminothienopyridines 1 can easily be N-acylated with ClCH₂C(O)Cl to give corresponding chloroacetamides 2 [18]. The yields are given in

Table 1. The prepared α-chloro-N-(thienopyridine-3-yl)acetamides 2.

N.	Compound	R	R1	R2	Yield, %
1	2a	Me	Me	OEt	93
2	2b	Me	Me	NHPh	84
3	2c	Me	Me	2,4-Me2C6H3NH	77
4	2d	Me	Me	5-Cl-2-MeC6H3NH	78
5	2e	Me	Me	4-Cl-2-MeC6H3NH	82
6	2f	Me	Me	4-BrC6H4NH	83
7	2g	Ph	Ph	NHPh	93
8	2h	Ph	4-MeOC6H4	NHPh	67

. The structure of several compounds 2 was proven by means of IR and NMR spectroscopy, including 2D NMR experiments (¹H-¹³C HSQC, ¹H-¹³C HMBC, ¹H-¹⁵N HMBC) (Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 and Figure 8). When chloroacetamides 2 were treated with Na₂S₂O₃ in aq. EtOH, the corresponding Bunte salts 3 were isolated with good yields (Scheme 1). Compounds 3 are colorless solids soluble in alcohol and water, and due to their solubility, they are useful in agrochemistry and pharmacy as prospective bioactive molecules.

3. Experimental Methods

Solvents and starting reagents were purified according to common procedures. Melting points were determined using a Stuart SMP30 device. IR spectra were recorded on a Bruker Vertex 70 instrument in ATR (attenuated total reflection) mode. ¹H, ¹³C DEPTQ, ¹H–¹³C HSQC, ¹H–¹³C HMBC, ¹H–¹⁵N HSQC, ¹H–¹⁵N HMBC NMR spectra were recorded on a Bruker Avance III HD spectrometer (400.17 MHz for ¹H, 100.63 MHz for ¹³C, and 40.55 MHz for ¹⁵N) in DMSO-d₆ using Me₄Si (δ = 0.0 ppm) as an internal standard for ¹H and ¹³C and nitromethane as a standard for ¹⁵N (δ = +380.23 ppm). Chemical shifts are given in parts per million (ppm), coupling constants are given in Hz, multiplicities are given as s (singlet), d (doublet), dd (doublet of doublets), m (multiplet) and br (broad). The purity of the compounds was checked by TLC (Sorbfil A plates) with hexane:AcOEt (1:1) or hexane:acetone (1:1) mixtures as eluents. The spots were visualized with iodine vapors, KMnO₄–H₂SO₄ solution or UV-light. Chloroacetyl chloride is commercially available (ACROS).

3.1. General Procedure for the Synthesis of α-Chloro-N-(thienopyridine-3-yl)acetamides 2

A round-bottom 100 cm³ flask was charged with the corresponding 3-aminothienopyridine 1 (8–10 mmol) and dry toluene (20–40 cm³). The mixture was warmed until the starting material had dissolved, and chloroacetyl chloride (1.1 eq., 8.8–11 mmol) was added dropwise. The reaction mixture was refluxed until the evolution of HCl had ceased and the starting amine was consumed (TLC control, 3–8 h). Then toluene was evaporated in vacuo, and the crude product was recrystallized or purified by boiling with an appropriate solvent.

3.2. Ethyl 3-(2-Chloroacetamido)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate (2a) (EWG = COOEt, R = R² = Me, R¹ = H)

Off-white solid, soluble in hot EtOH, yield 93%, m.p. 210 °C; FTIR (ATR): ν = 3236 (N–H), 1716 (C=O_ester), 1672 (C=O_amide) cm⁻¹; ¹H-NMR (400 MHz, DMSO-d₆): δ 1.29 (t, 3H, ³J = 6.9 Hz, OCH₂CH₃), 2.55 (s, 3H, C(6)CH₃), 2.58 (s, 3H, C(4)CH₃), 4.29 (q, 2H, ³J = 6.9 Hz, OCH₂CH₃), 4.36 (s, 2H, CH₂Cl), 7.19 (s, 1H, H-5), 10.34 (s, 1H, CONH) ppm; ¹³C DEPTQ NMR (101 MHz, DMSO-d₆): δ 14.1* (CH₂CH₃), 18.5* (C(4)CH₃), 24.0* (C(6)CH₃), 42.7 (CH₂Cl), 61.5 (OCH₂), 123.2* (C-5), 123.6 (C-2), 126.7 (C-3a), 133.6 (C-3), 145.0 (C-4), 158.3 (C-7a), 159.4 (C-6), 161.1 (C=O_ester), 166.2 (C=O_amide) ppm. *Anti-phase signals. ¹⁵N NMR (41 MHz, DMSO-d₆): δ 120.8 (NH), 288.7 (N-7) ppm.

3.3. Preparation of Compound 3a (EWG = COOEt, R = R² = Me, R¹ = H)

The starting ethyl 3-(chloroacetamido)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate (1) (0.01 mol) was dissolved in hot EtOH (20 mL), and a solution of an excess sodium thiosulfate (0.02 mol) in water (10 mL) was added. Then, the reaction mixture was boiled under reflux for 5 h (checked for completion by TLC). To isolate the product, the solvent was distilled off, resulting in the precipitation of a white crystalline solid. The resulting crude product 3 was filtered off and washed with a small amount of acetone to give pure Bunte salt 3 as colorless crystals; the yield was 30%. The compound is readily soluble in water and aq. EtOH, and slightly soluble in acetone and diethyl ether. The IR spectrum of compound 3a is given below (Figure 9).