(Z)-6-((Dimethylamino)methylene)-2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one

Abstract

Imidazothiazoles are important and attractive scaffolds for the design of potential biologically active small molecules. Dialkylenamines are convenient building blocks and are often used as intermediate reagents for the synthesis of various heterocyclic systems such as pyrimidine, pyridine, pyrazole, etc. In the present paper, the simple and effective synthesis of (Z)-6-((dimethylamino)methylene)-2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one (2) is reported. The proposed method, based on the reflux of 2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one with N,N-dimethylformamide dimethyl acetal, leads to an 80% yield of title compound 2. The structure of the synthesized compound 2 was confirmed using ¹H, ¹³C NMR, and LC-MS spectra. The applied protocol demonstrates practical advantages such as the absence of a solvent, a simple work-up, and the possibility of scale-up.

1. Introduction

Imidazothiazoles are a well known class of heterocyclic compounds that are of great importance to medicinal chemistry needs [1,2,3,4]. Among these heterocycles, partially hydrogenated derivatives and analogs are of special interest due to the increasing sp³ atom fraction, which impacts the pharmacodynamic and targets the binding properties of molecules [5]. This group of molecules is mostly known for the drug Levamisole, an active antihelmintic agent widely used for treating parasitic worm infections. Nowadays, derivatives with a wide spectrum of pharmacological properties including agents for the treatment of cancer [6,7,8,9] and other serious diseases [10,11,12,13,14] were identified among imidazothiazoles. On the other hand, imidazothiazoles could be considered bioisosteres of fused heterocyclic systems like thiazolo[3,2-b][1,2,4]triazoles and imidazo[2,1-b][1,3,4]thiadiazoles, which are also significant sources of potential drug-likeness molecules [15,16].

Compounds containing enamine/enaminone and dialkylamino moieties are efficient precursors for the synthesis of different types of heterocyclic systems [17,18]. Moreover, often the introduction of an enamine linker is a strategy for the structural optimization of hit/lead compounds providing favorable molecular properties. 1,1-Dimethoxy-N,N-dimethylmethanamine (DMF-DMA) is one of the most popular and easiest reagents used by synthetic chemists for obtaining the corresponding dimethylamino-methylene derivatives [17,18].

In this paper, we report a straightforward protocol for the synthesis of (Z)-6-((dimethylamino)methylene)-2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one (2), which may be used as a promising reagent in organic and medicinal chemistry. The structure of the compound is fully characterized by NMR spectroscopy and LC-MS spectrometry. The synthesized compound 2 can be used as a convenient and efficient precursor in dimethylamine substitution reactions with indole derivatives, as described in [19], for related heterocyclic systems to obtain aplysinopsin analogs. In addition, compound 2 can be used in condensation reactions with methylene-active compounds for the synthesis of new fused heterocyclic systems, as reported in [20].

2. Results and Discussion

Synthesis of the Title Compound 2

Using DMF-DMA for the synthesis of corresponding enamines in reaction with methylenactive compounds is widely popular, and different conditions for the reaction process were reported depending on the substrate type used in the reaction [21,22,23,24,25,26]. Despite the simplicity of the process, very often, difficulties could be met with targeted product elimination from the reaction mixture, as well as the selectivity of the reaction. Following the strategy and methodology of “green chemistry” [27] for the synthesis of the title compound, we used a solvent-free approach. The synthetic protocol reported in [20] was used, with some optimization for the synthesis of compound 2. The reaction conditions were optimized by using an equimolar amount of DMF-DMA and 2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one (1) and reducing the heating time to 7 h, as seen in Scheme 1. Under the aforementioned reaction conditions, compound 2 was obtained with the best yield (80%). The process was monitored by TLC, and extending the heating time and using excess DMF-DMA led to the formation of by-products that could not be identified and which caused additional difficulties in isolating the main product.

The obtained compound 2 was isolated in crystalline form and further purified by recrystallization, which allowed the avoidance of chromatographic procedures and makes the method convenient for scaling up.

The structure of the synthesized compound 2 was confirmed by ¹H, ¹³C, 2D NMR and LC-MS spectra (copies of spectra are presented in the Supplementary Materials), and key data are highlighted in Figure 1. Considering the chemical properties of DMF-DMA and the presence of several reactive centers in molecule 1, the formation of several hypothetical reaction products is possible, as depicted in Scheme 1. The molecular ion peak observed at the m/z value of 212.0 [M+H]⁺ in positive ionization mode in the mass spectrum excluded the formation of the theoretically possible compound 4. The presence of a doublet signal in the ¹H NMR spectrum at 1.55 ppm corresponds to the methyl group protons at position 2 of the heterocyclic system and excludes the formation of compound 3. Protons of the thiazolidine ring resonate as a multiplet at 4.23–4.31 ppm and a pair of doublet of doublets at 3.47 and 3.97 ppm with corresponding spin–spin coupling constants (²J = 10.8 and 11.0 Hz; ³J = 6.6 and 6.8 Hz) (Figure 1). Signals of methyl groups protons of –N(CH₃)₂ moiety appear as singlets at 3.13 and 3.42 ppm. Ylidene proton gives a singlet at 6.86 ppm.

In the ¹³C NMR spectrum, the signals of all carbon atoms are presented (Figure 1). Carbon atoms in the thiazolidine ring give signals at 47.4 (C2) and 48.3 (C3) ppm. Bridgehead carbon at C7a gives a signal at 152.7 ppm. The signals of three methyl group carbons appear at 20.9 (CH₃), 39.3 (NCH₃), and 46.0 (NCH₃) ppm correspondingly. The carbon signal of the carbonyl group (C=O) appears at 167.2 ppm. Ylidene carbon gives a signal at 138.5 ppm and carbon at C6 of the imidazoline ring resonates at 119.9 ppm.

The use of HMBC and HSQC techniques allowed for the confirmation of signal assignments based on 1D NMR techniques (Figure 1). The ³J_C-H value for the ylidene proton and the carbonyl group carbon atom (C5) within 3 Hz in the proton-coupled 13C NMR spectrum indicates the Z orientation of the ylidene moiety in the synthesized compound 2.

3. Materials and Methods

Melting points were measured in open capillary tubes on a BÜCHI B-545 melting point apparatus (BÜCHI Labortechnik AG, Flawil, Switzerland) and were uncorrected. The elemental analyses (C, H, and N) were performed using the Perkin-Elmer 2400 CHN analyzer (PerkinElmer, Waltham, MA, USA) and were within ±0.4% of the theoretical values. The 500 MHz ¹H and 125 MHz ¹³C NMR spectra were recorded on a Varian Unity Plus 500 (500 MHz) spectrometer (Varian Inc., Palo Alto, CA, USA). All spectra were recorded at room temperature, except where indicated otherwise, and were referenced internally to solvent reference frequencies. Chemical shifts (δ) are quoted in ppm and coupling constants (J) are reported in Hz. LC-MS spectra were obtained on a Finnigan MAT INCOS-50 (Thermo Finnigan LLC, San Jose, CA, USA). The reaction mixture was monitored by thin-layer chromatography (TLC) using commercial glass-backed TLC plates (Kieselgel 60 F254, Merck KGaA, Darmstadt, Germany). Solvents and reagents that are commercially available were used without further purification. The 2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one 1 was prepared according to the method described in [28].

(Z)-6-((Dimethylamino)methylene)-2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one (2)

A mixture of 2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one 1 (1.56 g, 10 mmol) and N,N-dimethylformamide dimethyl acetal (1.19 g, 10 mmol) was heated under reflux conditions for 7 h (monitored by TLC). After the completion of the reaction, the mixture was cooled to room temperature and evaporated to obtain a pure white-yellow solid of 2. Formed solid of 2 was recrystallized from methyl tert-butyl ether (MTBE).

Yield 80%, white-yellow crystal powder, mp 142–144 °C (MTBE).

¹H NMR (500 MHz, CDCl₃, δ): 1.55 (d, ²J = 6.0 Hz, 3H, CH₃), 3.13 & 3.42 (2*s, 6H, 2*NCH₃), 3.47 (dd, ²J = 11.0, ³J = 6.6 Hz, 1H, CH₂), 3.97 (dd, ²J = 10.8, ³J = 6.8 Hz, 1H, CH₂), 4.23–4.31 (m, 1H, CH), 6.86 (s, 1H, CH=).

¹³C NMR (125 MHz, CDCl₃, δ): 20.9 (CH₃), 39.3 (NCH₃), 46.0 (NCH₃), 47.4 (C2), 48.3 (C3), 119.9 (C6), 138.5 (CH=), 152.7 (C7a), 167.2 (C=O).

LCMS (Electrospray ionization (ESI+)): m/z 212.0 (100%, [M+H]⁺).

Anal. calc. for C₉H₁₃N₃OS: C, 51.41%, H, 6.13%; N, 20.01%; Found: C, 51.60%, H, 6.30%, N, 20.20%.

4. Conclusions

In the present work, we reported an efficient synthetic protocol for the synthesis of a new dimethylenamine-bearing imidazothiazole affording the title compound in good yield without the need for catalysts or extensive purification steps. These advantages make the method attractive for further application in the synthesis of structurally related derivatives. The structure of the compound was characterized and elucidated using NMR spectroscopy and LC-MS spectrometry analysis. The reported compound is a useful building block for the needs of synthetic organic and medicinal chemistry.