Ferrocenyl imidazolo[2,1- b ]-1,3,4-thiadiazoles: A microwave-assisted catalyst-free synthesis,characterization,and biological activities

Abstract

Ferrocenyl imidazolo[2,1-b]-1,3,4-thiadiazoles are synthesized using 2-amino-5-substituted-1,3,4-thiadiazole and α-bromoacetyl ferrocene as substrates under microwave-assisted and catalyst-free conditions. The structures are characterized by infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, mass spectrometry, and elemental analysis. Compared with conventional methods, the present protocol has the advantages of being rapid, efficient, environmentally friendly, and low cost. The results of biological activity studies showed that the products displayed better activities than those of 2-amino-5-substituted-1,3,4-thiadiazole. The biological activities of compounds in which R = phenyl were better than those with alkyl groups. Compounds with electron-withdrawing groups on the aryl moiety showed increased biological activities.

Keywords

imidazole thiadiazole ferrocene microwave-assisted catalyst-free

Introduction

Imidazolo[2,1-b]-1,3,4-thiadiazole derivatives were first discovered in 1952.¹ The near-planar and molecular rigid structure conferred them with distinctive physicochemical and biological properties. Significant progress has been made with these compounds in the field of pharmaceutical applications with continuous in-depth studies of this heterocyclic system in biology and chemistry. In the design process of modern drugs, it was discovered that imidazo[2,1-b]-1,3,4-thiadiazole derivatives display selective inhibition toward several receptors and enzymes, thus making them interesting as lead targets for potential drugs.

A large number of imidazo[2,1-b]-1,3,4-thiadiazole derivatives have been found to show various biological activities, including antituberculosis,^2,3 antibacterial,^4–6 anticancer,^7,8 and anti-inflammatory.^9,10 The imidazo[2,1-b]-1,3,4-thiadiazole moiety is relatively stable but examples in which the 2,5 and 6 positions contain a C–H bond can undergo electrophilic substitution,⁷ nucleophilic substitution, nitration,¹¹ and the Vilsmeier–Haack reaction.¹² Imidazo[2,1-b]-1,3,4-thiadiazoles can also coordinate with metals to form complexes¹³ or be used in its ring-opening reactions¹¹ under specific conditions.

Up to now, imidazo[2,1-b]-1,3,4-thiadiazoles are mostly obtained by ring-forming reactions of 1,3,4-thiadiazole compounds and α-haloketones. The traditional method involves refluxing a mixture of a 1,3,4-thiadiazole and α-haloketone in an alcohol solvent for several hours (intermolecular reaction) followed by intramolecular cyclization to give imidazo[2,1-b]-1,3,4-thiadiazoles. With the development of different organic synthesis technologies, ionic liquid-catalyzed¹⁴ and microwave-assisted reactions⁸ have also been applied for the synthesis of imidazo[2,1-b]-1,3,4-thiadiazoles. Compared with traditional methods, these approaches improve the reaction efficiency.

In recent years, our group has focused on the development of green organic synthesis technologies,^15–19 and herein, we have developed a microwave-assisted method to synthesize imidazo[2,1-b]-1,3,4-thiadiazoles (Scheme 1). Importantly, the present protocol did not need any catalyst, and the reaction efficiency was very high under the given conditions. A series of novel ferrocenyl imidazo[2,1-b]-1,3,4-thiadiazoles, which were characterized by infrared (IR), 1H nuclear magnetic resonance (NMR), 13C NMR, mass spectrometry (MS), and elemental analysis, were obtained. Furthermore, the biological activities of the prepared compounds were explored.

Scheme 1.

The synthesis of ferrocenyl imidazo[2,1-b]-1,3,4-thiadiazoles 3a-m.

Results and discussion

Synthetic mechanism

The ferrocenyl imidazo[2,1-b]-1,3,4-thiadiazoles were synthesized by an intermolecular nucleophilic substitution reaction and an intramolecular nucleophilic addition reaction of 2-amino-5-substituted-1,3,4-thiadiazoles and α-bromoacetyl ferrocene. First, the secondary amine was formed by nucleophilic substitution of α-bromoacetyl ferrocene and 2-amino-1,3,4-thiadiazole. An intramolecular nucleophilic addition reaction then yielded the intermediate product. Finally, ferrocenyl imidazo[2,1-b]-1,3, 4-thiadiazoles 3 were obtained by dehydration of the intermediates (Scheme 2).

Scheme 2.

The mechanism for synthesis of ferrocenyl imidazo[2,1-b]-1,3,4-thiadiazoles.

Optimization of the reaction conditions

The conventional method for the synthesis of 2-substituted-6-ferrocenyl-imidazo[2,1-b]-1,3,4-thiadiazoles requires a high temperature and long reaction time and is generally refluxed in an alcohol for 12–14 h. In addition, due to the limitations, the overall yield was low, the probability of side reactions is greatly increased, and the by-products generated are difficult to remove.

Heating in a microwave oven transfers electromagnetic energy to the inside of a heated substance.²⁰ The frictional collisions between molecules generate thermal energy to increase the temperature of the substance. Using microwave-assisted synthesis, the energy is directly applied to the internal system of the reacting molecules, thereby making the energy utilization more effective to improve the reaction efficiency, greatly accelerate the reaction speed, shorten the reaction time, and reduce the occurrence of side reactions. Microwave-assisted synthesis can greatly reduce the reaction time (about 10 min) and also lowers the reaction temperature,²¹ which effectively reduces the incidence of side reactions. At the same time, it has the advantages of convenient operation and low cost. A comparison between the conventional and microwave-assisted methods for the synthesis of compounds 3 is given in Table 1.

Table 1.

Comparison of the synthesis of 3a-m under conventional and microwave-assisted methods.^a


Product	R	Conventional method		Microwave-assisted method
Product	R	Time (h)	Yield (%)^b	Time (min)	Yield (%)^b
3a	H	10	53	12	79
3b	Me	10	54	12	87
3c	Et	10	53	12	86
3d	Pr	10	59	12	93
3e	CH₂Cl	12	55	12.5	86
3f	CH=CH₂	12	57	12.5	91
3g	Ph	12	55	12.5	76
3h	4-O₂N-C₆H₄	14	58	13	96
3i	4-H₂N-C₆H₄	12	60	12.5	84
3j	3-H₂N-C₆H₄	12	63	12.5	78
3k	4-Cl-C₆H₄	14	60	13	74
3l	4-F₃C-C₆H₄	14	55	13	89
3m	4-pyridyl	12	55	12.5	75

Reaction conditions: 2-amino-5-substituted-1,3,4-thiadiazole (1 mmol) and α-bromoacetyl ferrocene (1 mmol).

The yield refers to that of pure product after recrystallization.

From Table 1, it can be seen clearly that when R was an alkyl group, the reaction time was shorter than that when R was an aryl group. The electron-donating effect of the alkyl group increased the electron cloud density on the N of the -NH₂, which favored the reaction for the nucleophilic substitution reaction with α-bromoacetyl ferrocene; hence the reaction time was shorter. In contrast, the reaction time when R was an electron-withdrawing aryl group was longer, and the nucleophilic substitution reaction with α-bromoacetyl ferrocene was more difficult.

Next, the effect of the catalyst on the yield of ferrocenyl imidazo[2,1-b]-1,3,4-thiadiazole (3a) under microwave-assisted conditions was explored (Table 2). It was found that the yield under the catalyst-free process was higher than that with a base (K₂CO₃, Et₃N, KOH, NaOH, and EtONa) as the catalyst. The reason was that although the nucleophilic substitution reaction used a base as the catalyst to facilitate the reaction, the presence of the base was not conducive to protonation of the nucleophilic addition product during the intramolecular nucleophilic addition stage; therefore the base was not beneficial to the reaction.

Table 2.

The effect of catalysts on the yield of 3a.^a


Entry	Catalyst	Time (min)	Yield (%)^b
1	–	12	79
2	K₂CO₃	15	71
3	Et₃N	15	68
4	KOH	15	71
5	NaOH	15	72
6	EtONa	15	70

Reaction conditions: 2-amino-1,3,4-thiadiazole (1 mmol) and α-bromoacetyl ferrocene (1 mmol).

The yield refers to that of pure product after recrystallization.

The effect of the solvent on the yield of 3a was also examined as shown in Table 3. Under certain conditions, the greater the polarity of the solvent, the higher the yield of 3a. At the same time, the yield in the presence of a protic solvent was higher than that obtained with an aprotic solvent. EtOH was the best solvent because it provides protons and also forms an azeotropic mixture with water to achieve the dehydration and produce the ring.

Table 3.

Effect of the solvent on the yield of 3a.^a


Entry	Solvent	Time (min)	Yield (%)^b
1	H₂O	12	56
2	EtOH	12	79
3	MeOH	12	78
4	DMF	12	60
5	MeCN	12	68
6	CHCl₃	15	58
7	CH₃COCH₃	15	67
8	DMSO	12	64
9	Benzene	15	44
10	Toluene	15	46
11	CCl₄	15	41

DMF: dimetyl formamide; DMSO: dimethyl sulfoxide.

Reaction conditions: 2-amino-1,3,4-thiadiazole (1 mmol) and α-bromoacetyl ferrocene (1 mmol).

The yield refers to that of pure product after recrystallization.

Biological activity

The synthesized compounds in the present study were screened in vitro for antibacterial and antifungal activity against various gram-positive and gram-negative bacteria, and fungal strains using the agar cup-plate method.^21,22 Tetracycline and fluconazole were used as standard drugs for antibacterial and antifungal activity, respectively, at concentrations of 3 g L⁻¹. The zones of inhibition for 1a-m, 2, and 3a-m, measured for various strains (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Aspergillus niger, and Aspergillus fumigatus), are summarized in Table 4.

Table 4.

Antibacterial and antifungal activity (concentration: used 3 mg mL⁻¹ in DMSO) of 1a-m, 2, and 3a-m (zone of inhibition (mm)^a).

Compound	Bacteria			Fungi
Compound	Staphylococcus aureus	Bacillus cereus	Escherichia coli	Aspergillus niger	Aspergillus fumigatus
1a	18	22	20	21	24
1b	17	19	18	20	22
1c	17	18	18	19	21
1d	15	17	15	18	19
1e	21	23	22	24	25
1f	22	24	21	24	25
1g	25	25	21	25	25
1h	28	27	25	25	24
1i	25	24	26	27	25
1j	27	28	25	26	25
1k	26	27	27	28	26
1l	29	29	29	28	27
1m	28	26	26	25	25
3a	21	24	24	23	25
3b	19	21	20	21	23
3c	19	20	20	20	21
3d	20	19	20	19	20
3e	23	24	24	25	26
3f	22	26	23	26	27
3g	26	25	23	25	26
3h	31	30	31	30	31
3i	29	29	29	28	29
3j	28	28	28	27	28
3k	31	30	29	29	29
3l	32	31	31	30	30
3m	20	29	29	28	28
2	25	23	22	26	25
DMSO	–	–	–	–	–
Tetracycline	25	24	25	–	–
Fluconazole	–	–	–	24	23

DMSO: dimethyl sulfoxide.

Zone of inhibition (mm): <20, weak; 20–25, moderate; >25, significant.

As can be seen from Table 4, the activities of 3a-m were better than those of 1a-m and 2. In both series, the activities of compounds when R was bearing phenyl substituents were better than those with R = alkyl groups. Compounds 3a-m showed better antibacterial activity than antifungal activity. Among all these compounds, 1h, 1i, 1j, 1k, 1l, 3h, 3i, 3j, 3k, and 3l displayed better biological activity. Compounds with electron-withdrawing groups on the aryl moiety (1h, 1k, 1l, 3h, 3k, and 3l) had increased the biological activities.

Conclusion

In summary, ferrocenyl imidazo[2,1-b]-1,3,4-thiadiazoles have been synthesized by a microwave-assisted method under catalyst-free conditions. The results showed that this method had the advantages of being rapid, gives high yields, adopts a simple method, and is environmentally friendly. The antibacterial and antifungal activity has also been studied with all the synthesized compounds showing interesting biological activities. Among them, aryl-substituted compounds were more active than alkyl-substituted examples. Compounds with electron-withdrawing aryl groups gave enhanced activities, and all compounds have better biological activity than the starting 2-amino-5-substituted-1,3,4-thiadiazoles.

Experimental

Materials and method

All chemicals were analytical grade and were used without further purification. The melting points were determined in an open glass capillary using a Titan TY1-0004 and are uncorrected. IR spectra (400–4000 cm⁻¹) were recorded on a Bruker Vector-22 FT-IR spectrometer with samples prepared as KBr pellets. The 1H NMR and 13C NMR spectra were recorded on a Bruker Avance-400 MHz spectrometer in DMSO-d₆ with tetramethylsilane (TMS) as an internal standard. MS were recorded on a Waters Ultima Global Spectrometer (ESI). The C, H, and N analyses were performed with a Fisons EA 1108 (CHNSO) elemental analyzer. Microwave reaction was carried out in a Honghu XH-MC-1 microwave reactor.

The 2-amino-5-substituted-1,3,4-thiadiazoles and α-bromoacetyl ferrocene were prepared as reported.^23,24

General procedure for conventional synthesis of the ferrocenyl imidazolo[2,1-b]-1,3,4-thiadiazoles 3

A mixture of 2-amino-5-substituted-1,3,4-thiadiazole (1 mmol), α-bromoacetyl ferrocene (1 mmol), and ethanol (5 mL) was refluxed for 10–12 h. After completion (monitored by thin-layer chromatography (TLC)), the solvent was removed by distillation and the obtained crude product was then purified by column chromatography using ethyl acetate hexane (3:1) to obtain the product 3.

General procedure for microwave-assisted catalyst-free synthesis of ferrocenyl imidazolo [2,1-b]-1,3,4-thiadiazoles 3

2-Amino-5-substituted-1,3,4-thiadiazole (1 mmol), α-bromoacetyl ferrocene (1 mmol), and ethanol (5 mL) were mixed uniformly in a dry crucible and then subjected to microwave irradiation of 700 W for 30 s. The crucible was removed from the microwave, ethanol (5 mL) was added, and then subjected to microwave irradiation; this process was repeated for 20–25 times until the reaction was complete (monitored by TLC). Then, the reaction was allowed to cool to room temperature. Water of 10 mL was added and the mixture was neutralized to pH 7–8 with saturated sodium carbonate solution. The obtained solid was filtered, washed with water, and dried. The crude product was recrystallized in dimetyl formamide (DMF) to afford 3a-m.

6-Ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3a): Orange-red solid; m.p. 278–280 °C; yield 79%. IR (KBr): 3081, 3013, 1556, 1427, 1141, 1063 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 4.23 (s, 5H), 4.59 (t, 2H, J = 7.2 Hz), 4.84 (t, 2H, J = 7.2 Hz), 8.05 (s, 1H), 8.56 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 155.3, 147.9, 138.2, 125.1, 57.7. ESI-MS: m/z = 310.06 [M + H]⁺. Anal. calcd. for C₁₄H₁₁FeN₃S: C, 54.39; H, 3.59; N, 13.59; found: C, 54.45; H, 3.87; N, 13.63.

2-Methyl-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3b): Brown solid; m.p. 256–258 °C; yield 87%. IR (KBr): 3093, 2965, 1533, 1375, 1194, 1070 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 2.74(s, 3H), 4.24 (s, 5H), 4.58 (t, 2H, J = 4.0 Hz), 4.79 (t, 2H, J = 6.8 Hz), 8.04 (s, 1H).13C NMR (101 MHz, DMSO-d₆): δ 149.9, 145.2, 137.6, 127.7, 60.2, 18.3. ESI-MS: m/z = 324.08 [M + H]⁺. Anal. calcd. for C₁₅H₁₃FeN₃S: C, 55.74; H, 4.05; N, 13.00; found: C, 55.70; H, 4.11; N, 13.13.

2-Ethyl-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3c): Brown solid; m.p. > 300 °C; yield 86%. IR (KBr): 3076, 2953, 1563, 1406, 834 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 1.35 (t, 3H, J = 7.2 Hz), 2.88 (q, 2H, J = 6.8 Hz), 4.28 (s, 5H), 4.64 (t, 2H, J = 8.0 Hz), 4.89 (t, 2H), 8.05 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 170.2, 147.2, 140.6, 120.6, 62.7, 23.1, 11.0. ESI-MS: m/z = 338.10 [M + H]⁺. Anal. calcd. for C₁₆H₁₅FeN₃S: C, 56.99; H, 4.48; N, 12.46; found: C, 57.07; H, 4.55; N, 12.49.

2-n-Propyl-6-ferrocenyl-imidazolo[2,1-b]-1,3,4-thiadiazole (3d): Brown solid; m.p. > 300 °C; yield 93%. IR (KBr): 3064, 2979, 2928, 1588, 1390, 1093 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 1.01 (t, 3H, J = 7.2 Hz), 1.80 (m, 2H, J = 7.2 Hz), 2.87 (t, 2H, J = 8.0 Hz), 4.22 (s, 5H), 4.60 (t, 2H, J = 3.2 Hz), 4.91 (t, 2H, J = 6.8 Hz), 8.02 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 177.9, 149.0, 142.3, 120.4, 62.1, 40.2, 22.1, 10.6. ESI-MS: m/z = 352.11 [M + H]⁺. Anal. calcd. for C₁₇H₁₇FeN₃S: C, 58.13; H, 4.88; N, 11.96; found: C, 58.19; H, 4.82; N, 11.91.

2-Chloromethyl-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3e): Orange-red solid, m.p. 287–289 °C; yield 86%. IR (KBr): 3046, 2970, 1760, 1392, 1114 cm⁻¹.1H NMR (CDCl₃, 400 MHz): δ 4.23 (s, 5H), 4.63(t, 2H, J = 3.2 Hz), 4.75(s, 2H), 5.01 (t, 2H, J = 8.0 Hz), 8.02 (s, 1H).13C NMR (101 MHz, DMSO-d₆): δ 180.2, 150.5, 144.2, 137.5, 59.9. ESI-MS: m/z = 358.99 [M + H]⁺. Anal. calcd. for C₁₅H₁₂ClFeN₃S: C, 50.37; H, 3.38; N, 11.75; found: C, 50.29; H, 3.40; N, 11.64.

2-Vinyl-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3f): Brown solid; m.p. 247–248 °C; yield 91%. IR (KBr): 3117, 3032, 1628, 1523, 1181 cm⁻¹.1H NMR (CDCl₃, 400 MHz): δ 4.26 (s, 5H), 4.59 (t, 2H, J = 8.4 Hz), 4.95 (t, 2H, J = 7.2 Hz), 5.19 (d, 1H, J = 16.0 Hz), 5.62 (d, 1H, J =10.4 Hz), 6.65 (m, 1H), 8.02 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 170.2, 144.9, 142.3, 134.7, 130.2, 121.3, 68.8. ESI-MS: m/z = 336.04 [M + H]⁺. Anal. calcd. for C₁₆H₁₃FeN₃S: C, 57.33; H, 3.91; N, 12.54; found: C, 57.25; H, 4.02; N, 12.48.

2-Phenyl-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3g): Brown solid; m.p. 258–261 °C; yield 76%. IR (KBr): 3120, 3073, 1597, 1508, 1393, 1014, 770 cm⁻¹.1H NMR (CDCl₃, 400 MHz): δ 4.29 (s, 5H), 4.56 (t, 2H, J = 7.2 Hz), 4.97 (t, 2H, J = 6.8 Hz), 7.33 (m, 5H), 8.02 (s, 1H).13C NMR (101 MHz, DMSO-d₆): δ 157.9, 150.8, 144.6, 138.6, 132.0, 131.2, 129.2, 127.5, 122.9, 57.9. ESI-MS: m/z = 386.10 [M + H]⁺. Anal. calcd. for C₂₀H₁₅FeN₃S: C, 62.35; H, 3.92; N, 10.91; found: C, 62.27; H, 3.87; N, 10.98.

2-(4-Nitrophenyl)-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3h): Brown solid; m.p. 276–279 °C; yield 96%. IR (KBr): 3032, 1587, 1538, 1477, 1088, 740 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 4.24 (s, 5H), 4.59 (t, 2H, J = 8.0 Hz), 5.04 (t, 2H, J = 8.4 Hz), 7.65 (m, 4H), 8.01 (s, 1H).13C NMR (101 MHz, DMSO-d₆): δ 160.2, 155.9, 148.6, 137.2, 130.7, 129.0, 122.6, 118.9, 62.7. ESI-MS: m/z = 431.08 [M + H]⁺. Anal. calcd. for C₂₀H₁₄FeN₄O₂S: C, 55.83; H, 3.28; N, 13.02; found: C, 55.89; H, 3.19; N, 13.10.

2-(4-Aminophenyl)-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3i): Brown solid; m.p. 258–261 °C; yield 84%. IR (KBr): 3374, 3301, 3258, 3027, 1532, 1423, 1083, 710 cm⁻¹.1H NMR (CDCl₃, 400 MHz) δ 4.27 (s, 5H), 4.59 (t, 2H, J = 7.2 Hz), 4.98 (t, 2H, J = 8.0 Hz), 6.27 (s, 2H), 7.37 (m, 4H), 8.03 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 167.9, 155.6, 152.7, 146.9, 133.7, 127.1, 125.5, 117.6, 111.2, 109.3, 59.9. ESI-MS: m/z = 401.11 [M + H]⁺. Anal. calcd. for C₂₀H₁₆FeN₄S: C, 60.01; H, 4.03; N, 14.00; found: C, 59.91; H, 4.06; N, 13.96.

2-(3-Aminophenyl)-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3j): Brown solid; m.p. 250–252 °C; yield 78%. IR (KBr): 3334, 3268, 3063, 1548, 1439, 1051, 768, 678 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 4.25 (s, 5H), 4.57 (t, 2H, J = 8.0 Hz), 4.76 (t, 2H, J = 6.8 Hz), 6.29 (s, 2H), 7.31 (m, 4H), 8.05 (s, 1H).13C NMR (101 MHz, DMSO-d₆): δ 157.2, 132.1, 137.6, 136.4, 131.9, 128.5, 125.5, 117.7, 116.9, 110.2, 109.9, 63.7. ESI-MS: m/z = 400.10 [M + H]⁺. Anal. calcd. for C₂₀H₁₆FeN₄S: C, 60.01; H, 4.03; N, 14.00; found: C, 60.04; H, 4.06; N, 14.04.

2-(4-Chlorophenyl)-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3k): Brown solid; m.p. 255–258 °C; yield 74%. IR (KBr): 3200, 3005, 1639, 1511, 1451, 1028, 833 cm⁻¹. 1H NMR (CDCl₃, 400 MHz) δ 4.28 (s, 5H), 4.56 (t, 2H, J = 3.2 Hz), 4.89 (t, 2H, J = 7.2 Hz), 7.34 (m, 4H), 8.03 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 163.1, 155.6, 148.9, 142.1, 137.6, 133.7, 129.4, 125.0, 59.2. ESI-MS: m/z = 420.99 [M + H]⁺. Anal. calcd. for C₂₀H₁₄FeClN₃S: C, 57.23; H, 3.36; N, 10.01; found: C, 57.28; H, 3.31; N, 10.08.

2-(4-Trifluoromethylphenyl)-6-ferrocenyl-Imidazolo [2,1-b]-1,3,4-thiadiazole (3l): Brown solid; m.p. > 300 °C; yield 89%. IR (KBr): 3105, 3050, 1607, 1513, 1473, 1089, 973, 830, 701 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 4.26 (s, 5H), 4.58 (t, 2H, J = 6.8 Hz), 5.06 (t, 2H, J = 6.8 Hz), 7.88 (m, 4H), 8.08 (s, 1H). 13C NMR (101 MHz, DMSO-d₆): δ 155.9, 152.9, 142.6, 140.7, 138.0, 130.4, 122.3, 120.5, 114.7, 65.2. ESI-MS: m/z = 454.08 [M + H]⁺. Anal. calcd. for C₂₁H₁₄F₃FeN₃S: C, 55.65; H, 3.11; N, 9.27; found: C, 55.57; H, 3.06; N, 9.20.

2-(4-Pyridyl)-6-ferrocenyl-Imidazolo[2,1-b]-1,3,4-thiadiazole (3m): Brown solid; m.p. 286–289 °C; yield 89%. IR (KBr): 3040, 1587, 1100, 916 cm⁻¹. 1H NMR (CDCl₃, 400 MHz): δ 4.26 (s, 5H), 4.59 (t, 2H, J = 3.2 Hz), 4.99 (t, 2H, J = 7.2 Hz), 8.06 (s, 1H), 8.66 (m, 4H). 13C NMR (101 MHz, DMSO-d₆): δ 166.2, 157.2, 150.6, 148.9, 138.2, 130.2, 116.9, 113.2, 70.2. ESI-MS: m/z = 387.09 [M + H]⁺. Anal. calcd. for C₁₉H₁₄FeN₄S: C, 59.08; H, 3.65; N, 14.51; found: C, 59.17; H, 3.72; N, 14.50.

Supplemental Material

supporting_information_6 – Supplemental material for Ferrocenyl imidazolo[2,1-b]-1,3,4-thiadiazoles: A microwave-assisted catalyst-free synthesis, characterization, and biological activities

Supplemental material, supporting_information_6 for Ferrocenyl imidazolo[2,1-b]-1,3,4-thiadiazoles: A microwave-assisted catalyst-free synthesis, characterization, and biological activities by Yuting Liu, Lan Yang and Dawei Yin in Journal of Chemical Research

Footnotes

Acknowledgements

The authors are thankful to the instrument analysis center of Shaanxi University of Science and Technology for Fourier-transform infrared (FTIR), 1H nuclear magnetic resonance (NMR), and elemental analysis.

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) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We are grateful for the financial support from the Natural Science Foundation of Shaanxi Province (2018JM7046).

ORCID iD

Yuting Liu

Supplemental material

The IR and 1H NMR spectrums of compounds 3a-m are available online.

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