A one-pot synthesis of 2-aminothiazoles via the coupling of ketones and thiourea using I 2 /dimethyl sulfoxide as a catalytic oxidative system

Abstract

A series of 2-aminothiazoles is prepared in moderate-to-good yields by the direct coupling of ketones and thiourea using I₂/dimethyl sulfoxide as a catalytic oxidative system. This method avoids the preparation of lachrymatory and toxic α-haloketones and the use of an acid-binding agent, thus providing a more convenient approach to 2-aminothiazoles compared to the Hantzsch reaction.

Keywords

2-aminothiazoles ketones synthesis thiourea

Thiazole is an important heterocycle and has found a broad spectrum of applications in fields from agriculture to medicine.^1–6 In particular, aminothiazole is a useful structural motif and is present in numerous compounds possessing diverse biological properties, including anticancer, anticonvulsant, antidiabetic, antiviral, and antituberculosis, among many others.^7–11 The aminothiazole backbone has been widely used as a privileged pharmacophore in the discovery of potential new chemical entities with diverse biological activities. Various drugs bearing an aminothiazole moiety with important therapeutic effects are now available, such as dasatinib, cefcapene, talipexole, meloxicam, and many others (Figure 1).^12–17

Figure 1.

Representative drugs with an aminothiazole unit.

Given these proven utilities in medicinal chemistry, considerable attention has been paid to the synthesis of 2-aminothiazoles. The Hantzsch reaction provides a practical approach to 2-aminothiazoles via the condensation reaction of α-haloketones and thioureas in a polar solvent.¹⁸ Subsequently, various modified Hantzsch methods have been developed such as using heterogeneous catalysts, microwave heating, solid synthesis, or greener solvents including ionic liquids, PEG-400, and water.^19–25 Other synthetic methods toward 2-aminothiazoles have utilized different coupling partners such as phenyl thiocyanates and propargylamines, alkyne(alkene)-substituted iodine(III) reagents and thioureas, 1,2-dicyano-3-bromo-2-phenylpropenes and thioureas, and α-SCN-substituted ketones and amines.^26–29 However, the preparation of these coupling materials is generally difficult, needing multiple steps and harsh reaction conditions.

Notwithstanding, the Hantzsch method and modified reactions still represent efficient approaches to 2-aminothiazoles due to the use of readily available α-haloketones and thioureas. However, the synthesis of lachrymatory and toxic α-haloketones makes these methods inconvenient. Recently, Abedi-Jazini et al.³⁰ reported a more convenient synthesis of 2-aminothiazoles via the I₂-mediated oxidative coupling of ketones and thiourea in the presence of an organic base. This method proceeded through the in situ formation of α-iodoketones and provided 2-aminothiazoles in high yields; however, the requirement of using stoichiometric I₂ as the oxidant and an organic base (such as NEt₃) as an acid-binding agent might limit its further use. In recent years, the I₂/dimethyl sulfoxide (DMSO) catalytic oxidative system has been successfully applied in various types of organic transformations.^31–35 In these methods, the I₂ catalytic cycle was completed using DMSO as the oxidant. We focused on utilizing this catalytic oxidative system in the Hantzsch method to achieve the one-pot synthesis of 2-aminothiazoles without the preparation of α-haloketones. Herein, we report the first example of I₂ catalytic synthesis of 2-aminothiazoles through the oxidative coupling of ketones and thiourea using DMSO as the solvent and oxidant.

We started our optimization studies by reacting 2 mmol each of acetophenone (1a) and thiourea (2) in DMSO (4 mL) at 50 °C using 20 mol% of I₂ as the catalyst. As shown in Table 1, the reaction gave the desired product 3a in 43% yield. Besides, this reaction also produced 4a in 27% yield as the major by-product (entry 1). The formation of dithiazole thioether 4a might result from the further reaction of 3a and thiourea (Wu’s group has reported the preparation of compound 4a; for details, see Xue et al.³⁶). Temperature screening indicated that the reaction conducted at 80 °C gave a higher yield of 3a and a lower amount of 4a (entries 2 and 3). The molar ratio of acetophenone to thiourea had a key effect on the reaction. Using 0.5 equiv. of acetophenone predominantly generated 4a in 47% yield (entry 4). In contrast, the reaction using 2 equiv. of acetophenone gave the desired product 3a in 50% yield (entry 5). Further increasing the amount of acetophenone resulted in a slightly lower yield of 3a (entry 6). The amount of I₂ was also investigated, as well as the effects of acid additives, other catalysts, solvents, and the reaction time (entries 7–17). It was observed that the addition of acid additives promoted the formation of 4a and in consequence led to 3a in very low yields (entries 10–12). Using an aqueous solution of HBr instead of I₂ or using DMSO/H₂O as the solvent both resulted in trace product with a mass of sulfur suspended in the reaction mixture (entries 14 and 15). Water existing in the reaction mixture might promote the formation of sulfur via oxidative desulfuration of thiourea. Based on the results of these screening experiments, the optimum reaction conditions were identified as 2 equiv. of acetophenone (1a), 1 equiv. of thiourea (2), and 0.2 equiv. of I₂ in DMSO at 80 °C for 12 h (entry 16).

Table 1.

Optimization of the reaction conditions.^a


Entry	1a (equiv.)	I₂ (mol%)	Temp (°C)	Reaction time (h)	Yield (%)^b
1	1	20	50	24	43 (27)
2	1	20	80	24	48 (18)
3	1	20	100	24	35 (29)
4	0.5	20	80	24	6 (47)
5	2	20	80	24	50 (trace)
6	4	20	80	24	48 (trace)
7	2	10	80	24	9 (trace)
8	2	30	80	24	36 (28)
9	2	50	80	24	10 (39)
10^c	2	20	80	24	20 (17)
11^d	2	20	80	24	Trace (35)
12^e	2	20	80	24	Trace (29)
13^f	2	20	80	24	0 (trace)
14^g	2	20	80	24	Trace (trace)^h
15ⁱ	2	20	80	24	Trace (trace)^h
16	2	20	80	12	53 (trace)
17	2	20	80	6	40 (trace)

Conditions: 1a, 2 (2 mmol), I₂, DMSO (4 mL).

Isolated yield of 3a. The isolated yields of 4a are shown in parentheses.

p-TsOH (1.0 equiv.) was added to the reaction mixture.

AcOH (1.0 equiv.) was added to the reaction mixture.

CH₃SO₃H (1.0 equiv.) was added to the reaction mixture.

Bromine (0.2 equiv.) was used instead of I₂.

Aqueous HBr (0.2 equiv.) was used instead of I₂.

Sulfur suspended in the reaction mixture was isolated.

DMSO (2mL) and H₂O (2mL) was used as the solvent.

With optimized conditions in hand, we proceeded to investigate the scope of the ketones. As shown in Table 2, a range of substituted acetophenones bearing various substituents (F, Cl, Br, CH₃, OCH₃, CH₃SO₂, and OH) on the phenyl moiety were suitable for the reaction, providing the corresponding thiazoles in moderate-to-good yields. Substituted acetophenones bearing neutral (H) or electron-withdrawing groups (F, Cl, Br, CH₃SO₂) at the ortho-, meta-, or para-position of the phenyl moiety reacted smoothly under the optimized conditions, giving the corresponding products in 40%–79% yields (3a–e, 3h, and 3j–l). In contrast, slightly lower yields of products 3 were obtained (31%–57%) when acetophenones containing electron-donating groups (CH₃, OH, and OCH₃) were used in the reaction (3f, 3g, 3i, 3m, and 3n). The position of the substituent on the phenyl moiety of the acetophenone had an impact on the transformation. For instance, as shown in Table 2, the yields of chloro-substituted thiazoles followed the order meta (3h, 79%) > para (3c, 51%) > ortho (3k, 43%). The yields of methyl-substituted thiazoles also followed the same tendency (3f, 3i, and 3m). Pinacolone and ethyl pyruvate were also compatible with the optimized conditions, providing the corresponding thiazoles in moderate yields (3o and 3p). 1,2-Disubstituted enthanones were also investigated. When propiophenone was used in the transformation under the optimized conditions, the desired thiazole 3q was produced in a quite low yield. Based on the assumption that the fully substituted thiazole 3q formed in the reaction would not further transform into a dithiazole thioether, a set of the modified conditions (footnote c in Table 2) was used and the yield of 3q was raised to 40%. Thus, the addition of 20 mol% of TsOH and 2 equiv. of thiourea significantly promoted the formation of 3q. When the modified conditions were applied to 1,2-diphenylethanone, the corresponding thiazole 3r was also obtained in a much higher yield (75%, entry 18).

Table 2.

Reaction scope of the ketones.^a


Entry	R¹	R²	Product	Yield (%)^b
1	C₆H₅ (Ph)	H	3a	53
2	4-F-C₆H₄	H	3b	55
3	4-Cl-C₆H₄	H	3c	51
4	4-Br-C₆H₄	H	3d	42
5	4-MeSO₂-C₆H₄	H	3e	56
6	4-Me-C₆H₄	H	3f	44
7	3,4-(MeO)₂-C₆H₃	H	3g	42
8	3-Cl-C₆H₄	H	3h	79
9	3-Me-C₆H₄	H	3i	57
10	2-F-C₆H₄	H	3j	52
11	2-Cl-C₆H₄	H	3k	43
12	2-Br-C₆H₄	H	3l	40
13	2-Me-C₆H₄	H	3m	33
14	2-OH-C₆H₄	H	3n	31
15	t-Bu	H	3o	40
16	EtOCO	H	3p	53
17	C₆H₅	CH₃	3q	40^c (20)
18	C₆H₅	C₆H₅	3r	75^c

Conditions: 1 (4 mmol), 2 (2 mmol), I₂ (20 mol%), DMSO (4 mL).

Isolated yields.

Conditions: 1 (2 mmol), 2 (4 mmol), I₂ (20 mol%), TsOH (20 mol%), DMSO (4 mL). The yield in parentheses was obtained using the optimized conditions listed in footnote a.

Based on the results of our experiments and previous literature,^18–25 we propose the following reaction pathway (Scheme 1). Briefly, acetophenone (1a) is converted into α-iodoketone A in the presence of the I₂ catalyst. Subsequent reaction of A with thiourea would then give the desired 2-aminothiazole 3a. In this reaction, the in situ formed HI is oxidized by DMSO to complete the I₂ catalytic cycle. Besides, it was observed that 3a could convert into dithiazole thioether 4a by further reacting with thiourea. The formation of 4a was detected in a control experiment involving the reaction of 2 mmol each of 3a and thiourea in DMSO in the presence of I₂ (20 mol%). Regarding the transformation of 3a into 4a, Wu’s group has disclosed similar results and a plausible mechanism.³⁶

Scheme 1.

A plausible reaction pathway.

In conclusion, we have developed the I₂-catalyzed synthesis of 2-aminothiazoles via the direct oxidative coupling of ketones and thiourea. This reaction proceeds through the formation of α-iodoketone and employs DMSO as the oxidant to complete the I₂ catalytic cycle. This method avoids the preparation of α-haloketones and the use of an acid-binding agent, thus providing a convenient approach to 2-aminothiazoles.

Experimental

NMR spectra were obtained on a Bruker Ascend TM600 or a Bruker AVANCE III 500 MHz spectrometer in CDCl₃ or DMSO-d₆ using TMS as the internal reference. Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given in Hz. All products were isolated by short-path chromatography on Qingdao Haiyang silica gel (200–300 mesh) eluting with a mixed solvent of petroleum ether (60–90 °C)/ethyl acetate (5/1, v/v). Melting points were recorded on a SGWX-4B melting point apparatus. Commercially obtained reagents and DMSO were used without further purification.

I₂-catalyzed coupling reaction of ketones and thiourea: general procedure

A Schlenk tube (20 mL) was charged with ketone 1 (4 mmol), thiourea (2) (2 mmol), I₂ (0.4 mmol) and DMSO (4 mL). The tube was sealed with a rubber septum and the reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction, the mixture was cooled to room temperature. Ethyl acetate (20 mL) and a saturated solution of NaHCO₃ (20 mL) were added and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with a saturated solution of NaCl (20 mL) and then dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure. The crude mixture was purified by chromatography on silica gel to yield the desired products.

2-Amino-4-phenylthiazole (3a): white solid; m.p. 120–122 °C (lit.³⁷ 114–118 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.80–7.79 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 6.74 (s, 1H), 5.33 (brs, 2H).

2-Amino-4-(4-fluorophenyl)thiazole (3b): white solid; m.p. 94–96 °C (lit.³⁸ 101–102 °C); ¹H NMR (500 MHz, CDCl₃): δ = 7.76–7.73 (m, 2H), 7.09–7.05 (m, 2H), 6.64 (s, 1H), 5.38 (brs, 2H).

2-Amino-4-(4-chlorophenyl)thiazole (3c): white solid; m.p. 165–167 °C (lit.³⁹ 163–164 °C); ¹H NMR (500 MHz, CDCl₃): δ = 7.71 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 5.14 (brs, 2H).

2-Amino-4-(4-bromophenyl)thiazole (3d): white solid; m.p. 176–178 °C (lit.³⁹ 180–181 °C); ¹H NMR (500 MHz, CDCl₃): δ = 7.66 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 5.03 (brs, 2H).

2-Amino-(4-(4-methylsulfonyl)phenyl)thiazole (3e): white solid; m.p. 244–245 °C (lit.⁴⁰ 246–247 °C); ¹H NMR (600 MHz, CDCl₃): δ = 8.00–7.96 (m, 4H), 6.95 (s, 1H), 5.07 (brs, 2H), 3.09 (s, 3H).

2-Amino-4-(4-methylphenyl)thiazole (3f): white solid; m.p. 119–120 °C (lit.³⁷ 126–128 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.68 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.67 (s, 1H), 5.42 (brs, 2H), 2.39 (s, 3H).

2-Amino-4-(3,4-dimethoxyphenyl)thiazole (3g): yellow solid; m.p. 200–202 °C (lit.⁴¹ 198–201 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.36 (s, 1H), 7.34 (dd, J = 8.4, 1.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 5.18 (brs, 2H), 3.96 (s, 3H), 3.92 (s, 3H).

2-Amino-4-(3-chlorophenyl)thiazole (3h): white solid; m.p. 126–127 °C (lit.⁴² 112 °C); ¹H NMR (500 MHz, CDCl₃): δ = 7.78 (t, J = 1.8 Hz, 1H), 7.64 (dt, J = 7.6, 1.8 Hz, 1H), 7.34–7.23 (m, 2H), 6.74 (s, 1H), 5.41 (brs, 2H).

2-Amino-4-(3-methylphenyl)thiazole (3i): white solid; m.p. 90–92 °C (lit.³⁹ 79–92 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.63 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.72 (s, 1H), 5.37 (brs, 2H), 2.41 (s, 3H).

2-Amino-4-(2-fluorophenyl)thiazole (3j): white solid; m.p. 88–90 °C; ¹H NMR (500 MHz, CDCl₃): δ = 8.02 (td, J = 7.8, 1.9 Hz, 1H), 7.26 (m, 1H), 7.19 (td, J = 7.8, 1.9 Hz, 1H), 7.12 (m, 1H), 7.02 (d, J = 2.2 Hz, 1H), 5.40 (brs, 2H). The ¹H NMR spectrum of compound 3j was consistent with that of literature.⁴³

2-Amino-4-(2-chlorophenyl)thiazole (3k): white solid; m.p. 135–137 °C; ¹H NMR (600 MHz, CDCl₃): δ = 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.24 (td, J = 7.8, 1.5 Hz, 1H), 7.04 (s, 1H), 5.30 (brs, 2H). The ¹H NMR spectrum of compound 3k was consistent with that of literature.⁴³

2-Amino-4-(2-bromophenyl)thiazole (3l): red solid; m.p. 130–131 °C (lit.⁴⁴ 123 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.70 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.94 (s, 1H), 5.32 (brs, 2H).

2-Amino-4-(2-methylphenyl)thiazole (3m): white solid; m.p. 90–93 °C (lit.³⁹ 81–82 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.55 (d, J = 6.7 Hz, 1H), 7.30–7.19 (m, 3H), 6.45 (s, 1H), 5.53 (brs, 2H), 2.47 (s, 3H).

2-Amino-4-(2-hydroxyphenyl)thiazole (3n): yellow solid; m.p. 136–138 °C (lit.³⁹ 139–140 °C); ¹H NMR (600 MHz, CDCl₃): δ = 11.59 (s, 1H), 7.56 (dd, J = 7.9, 1.0 Hz, 1H), 7.22 (dd, J = 11.0, 4.2 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.87 (dd, J = 11.0, 4.2 Hz, 1H), 6.77 (s, 1H), 5.11 (s, 2H).

2-Amino-4-(t-butyl)thiazole (3o): white solid; m.p. 105–107 °C (lit.³⁹ 98–99 °C); ¹H NMR (600 MHz, CDCl₃): δ = 6.07 (s, 1H), 5.64 (brs, 2H), 1.26 (s, 9H).

Ethyl 2-Aminothiazole-4-carboxylate (3p): white solid; m.p. 170–172 °C (lit.⁴⁵ 171–174 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.42 (s, 1H), 5.82 (brs, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

2-Amino-5-methyl-4-phenylthiazole (3q): yellow solid; m.p. 108–110 °C (lit.⁴⁶ 115–116 °C); ¹H NMR (500 MHz, CDCl₃): δ = 7.58–7.56 (m, 2H), 7.42–7.39 (m, 2H), 7.33–7.27 (m, 1H), 5.11 (brs, 2H), 2.40 (s, 3H).

2-Amino-4,5-diphenylthiazole (3r): yellow solid; m.p. 179–182 °C (lit.³⁹ 184–185 °C); ¹H NMR (600 MHz, CDCl₃): δ = 7.49–7.47 (m, 2H), 7.31–7.25 (m, 8H), 5.23 (brs, 2H).

5,5′-Thiobis(4-phenylthiazole-2-amine) (4a): Compound 4a was isolated by flash chromatography (silica gel, petroleum ether/ethyl acetate, 1/1); yellow solid, m.p. 194–196 °C (lit.³⁶ 208.9–212.6 °C); ¹H NMR (500 MHz, DMSO-d₆): δ = 7.74–7.72 (m, 4H), 7.34–7.32 (m, 10H); ¹³C NMR (125 MHz, DMSO-d₆): δ = 168.5, 152.4, 134.0, 128.6, 128.0, 109.8. The spectral data of compound 4a are in accordance with the literature.³⁶

Supplemental Material

SI – Supplemental material for A one-pot synthesis of 2-aminothiazoles via the coupling of ketones and thiourea using I2/dimethyl sulfoxide as a catalytic oxidative system

Supplemental material, SI for A one-pot synthesis of 2-aminothiazoles via the coupling of ketones and thiourea using I2/dimethyl sulfoxide as a catalytic oxidative system by Qian Zhang, Jiefei Wu, Zexi Pan, Wen Zhang and Wei Zhou in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Wei Zhou

Supplemental material

Supplemental material for this article is available online.

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A one-pot synthesis of 2-aminothiazoles via the coupling of ketones and thiourea using I 2 /dimethyl sulfoxide as a catalytic oxidative system

Abstract

Keywords

Experimental

I2-catalyzed coupling reaction of ketones and thiourea: general procedure

Supplemental Material

SI – Supplemental material for A one-pot synthesis of 2-aminothiazoles via the coupling of ketones and thiourea using I2/dimethyl sulfoxide as a catalytic oxidative system

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material

I₂-catalyzed coupling reaction of ketones and thiourea: general procedure