3-Ethyl-2-(ethylimino)-4-methyl-2,3-dihydro-1,3-thiazole-5-carboxylate Ethyl Ester

Abstract

An efficient procedure to obtain the new compound 1a from ethyl acetoacetate (2a), NBS and N,N′-diethylthiourea (4a) was reported. In comparison with the traditional method to synthesize its analogues, this efficient, catalyst-free, and one-pot synthetic method is facile. The work-up procedure is easy and gives the pure target compound under milder reaction conditions in a relatively high yield of 75%.

1. Introduction

In view of the importance of functionalized 2,3-dihydrothiazole derivatives in both the organic synthesis [1] and the biological fields [2], several preparation methods have been developed [3,4,5,6]. The traditional synthetic route to this type of skeleton (1) usually involves two steps from β-keto esters (2), a halogenated reagent such as N-bromosuccinamide (NBS) or N-chlorosuccinamide (NCS), and thiourea or its derivatives (4) (Scheme 1) [7]. This method usually involves the tedious purification procedures of the halogenated intermediates (3a and 3b). In order to obtain diversely substituted 2,3-dihydrothiazole-4-carboxylate esters efficiently, an improved method employed isothiocyanate, primary alkylamine, and 2-chloro-1,3-dicarbonyl compounds as the starting materials [8]. The latter material could be changed into β-nitroacrylates in ionic liquid [9]. The main material isothiocyanates of those methods usually need to be synthesized and purified ahead of the usage, which hampers the wide use of this method. Recently, a method to synthesize 1,3-thiazol-2-imine derivatives from benzoylphenylthioureas and α-bromoketones generated in situ from the reaction of enolizable ketones with 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT, or 1,2-dipyridinium ditribromide-ethane, DPTBE) has been reported [10,11].

The attempt in our research group to acquire the title compound—3-ethyl- 2-ethylimino-4-methyl-2,3-dihydro-1,3-thiazole-5-carboxylate ethyl ester (1a)—using the reported DBTBE method led to the complete recovery of the starting materials. The conventional synthesis of 1a via Scheme 1 involved a tedious work-up with very low overall yield, which could not be used efficiently.

As part of our recent studies on the new biological heterocyclic compounds [12,13], we now report a successful simple procedure to synthesize 1a from ethyl acetoacetate (2a), NBS, and N,N′-diethylthiourea (4a). While 1a shares a similar structure with the reported analogues [8], it was still reported for the first time by our research group in this paper.

Comparing with the traditional method of synthesizing its analogues, this efficient, catalyst-free, and one-pot synthetic method is facile; the work-up procedure is easy and gives the pure target compound under milder reaction conditions with a relatively high yield of 75%. This method offers an alternative way to provide 2,3-diethyl-2,3-dihydro-1,3-thiazole (1a) instead of the traditional two-step method from disubstituted thioureas and β-keto ester derivatives (Scheme 2).

The methods developed in this paper will enrich the limited arsenal for efficiently constructing various functionalized 2,3-dihydro-1,3-thiazoles, which would be a benefit for further exploration of their potent unknown biological activities. In addition, this method is expected to be useful for the expedient synthesis of a variety of heterocyclic compounds with a thiazole core in more complex structures other than the simple substituted 1a.

2. Experimental Section

Melting points were taken on an X-4 digital melting point apparatus (Shanghai Yice Apparatus & Equipments Co., Ltd, Shanghai, China) and are uncorrected. Elemental analyses were performed on a Carlo-Erba 1106 elemental analyzer (Thermo Scientific, Waltham, MA, USA). IR spectra were recorded on a Nicolet FT-IR 360 spectrophotometer (Thermo Scientific, Waltham, MA, USA). ¹H-NMR and ¹³C-NMR spectra were determined on a Bruker AM-400 (400 MHz) spectrometer (Brucker Company, Fällanden, Switzerland) with tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in δ. Mass spectra were measured on a HP5988A instrument (Hewlett-Packard, Palo Alto, CA, USA) by direct inlet at 70 eV. All materials were obtained from commercial suppliers and used as received.

Ethyl 3-ethyl-2-(ethylamino)-2,3-dihydro-4-methylthiazole-5-carboxylate (1a)

To a mixture of ethyl acetoacetate (2, 6.50 g, 50.0 mmol) in water (30.0 mL) and tetrahydrofuran (THF) (28.0 mL) cooled to −5–0°C was added NBS (10.7 g, 60.0 mmol, 1.20 equiv.). The reaction mixture was stirred at room temperature for 1.0 h, and thin-layer chromatography (TLC, petroleum ether-ethyl acetate v/v = 2:1) showed the disappearance of 2. N,N′-diethylthiourea (4a, 6.60 g, 50.0 mmol, 1.00 equiv.) was added, and the reaction mixture was heated to 95 °C for 19 h. After cooling to room temperature, the reaction mixture was filtered to remove an insoluble red precipitate, and then NH₃^.H₂O (8.0 mL) was added to the filtrate. The resulting yellow solid was collected via filtration under the reduced pressure. The filter cake was washed with water (100 mL × 3), recrystallized from ethyl acetate, then dried to give the target compound as the yellow cubic crystals (1a, 9.10 g, 75%), mp. 63–64 °C, ¹H-NMR (CDCl₃, 400 MHz): δ 1.23–1.29 (m, 6H, NCH₂CH₃× 2), 1.33 (t, 3H, OCH₂CH₃), 2.57 (s, 3H, thiazole-4-CH₃), 3.17 (q, 2H, 3-N-CH₂CH₃), 3.89 (q, 2H, 2-N-CH₂CH₃), 4.26 (q, 2H, OCH₂CH₃); ¹³C-NMR (100 MHz, CDCl₃): δ 12.72 (thiazole-4-CH₃), 13.32 (thiazole-3-N-CH₂CH₃), 14.38 (-OCH₂CH₃),15.36 (=NCH₂CH₃), 38.82 (thiazole-3-NCH₂CH₃), 48.91 (=NCH₂CH₃), 60.41 (OCH₂CH₃), 98.62 (thiazole-5-C),147.16 (thiazole-2-C), 155.74 (thiazole-4-C), 162.38 (O=C). MS: m/z 243 (M + H⁺). Elemental Analysis. Calcd for C₁₁H₁₈N₂O₂S: C, 54.52; H, 7.49; N, 11.56. Found: C, 54.41; H, 7.36; N, 11.42.

3. Conclusions

To summarize, a new compound with the name of 2-ethyl-2-ethylimino-4-methyl-2,3-dihydro- 1,3-thiazole-5-carboxylate ethyl ester was synthesized efficiently via an improved one-pot reaction with a relatively high yield. This method might be useful in further synthesis of the compounds with the similar structure skeleton.