Remarkably high-speed synthesis of 2-substituted amino-4-aryl thiazoles in polar solvents with a minimum threshold polarity index of 4.8 was found to proceed to completion in just 30–40 sec. affording excellent yields of thiazoles under ambient temperature conditions without the use of any additional catalyst. The purification-free procedure afforded libraries based around a known pharmacophore, namely, substituted arylthiazoles and generated samples of high purity. In terms of combinatorial synthesis in a single solution phase, our protocol is significantly better than those hitherto reported and is amenable for HTS. The
Thiazole and its derivatives are very useful compounds in various fields of chemistry including medicine and agriculture. For example, the thiazolium ring present in vitamin B1 serves as an electron sink, and its coenzyme form is important for the decarboxylation of
In view of the importance of 2-aminothiazole and its derivatives, several methods have been reported in the literature. Hantzsch reaction of
We extended the investigation of this solvent system towards the synthesis of 2-aminothiazoles by the reaction of phenacyl bromides
The reaction of phenacyl bromides
In order to highlight the role of DMSO in the scheme, various other dipolar aprotic solvents were also screened along with the IL in the proportion of 1 : 0.1 for the model reaction of phenacyl bromide with thiourea. The results are recorded in Table
Screening of IL in combination with various dipolar aprotic solvents.
Sr. no. | IL+ dipolar aprotic solvents | Reaction time (sec) |
---|---|---|
1 | (bbim)+Br + DMSO | 30–40 |
2 | (bbim)+Br + DMF | 30–40 |
3 | (bbim)+Br + acetonitrile | 30–40 |
4 | (bbim)+Br + Dioxane | 60 |
It was found that under similar conditions, all the dipolar aprotic solvents afford the products in the same yields and reaction times as was found for the DMSO: IL system. It was then surmised whether IL is required at all in the reaction with the dipolar aprotic solvents individually contributing to the minimum polarity index of the media responsible for inducing the reaction. To our surprise, all dipolar aprotic solvents individually also gave excellent yields in just 30–40 sec. The performances of the solvents are recorded in Table
Screening of solvents for reaction.
Sr. no. | Solvents | Polarity index | Reaction time |
---|---|---|---|
1. | DMSO | 7.2 | 25–30 sec |
2. | DMF | 6.4 | 30–40 sec |
3. | Acetonitrile | 5.8 | 30–40 sec |
4. | Ethanol | 5.2 | 60 sec |
5. | Methanol | 5.1 | 60 sec |
6. | Dioxane | 4.8 | 60 sec |
7. | n-butanol | 4.0 | 90 sec |
8. | Dichloromethane | 3.1 | 4 min |
9. | Carbon tetrachloride | 1.6 | Not going even after 30 min |
Herein, an assumption was made that a solvent with a minimum threshold polarity index [
Thus, after having examined the scope of this method in various solvents, since DMSO afforded the best results, all further reactions were carried out in DMSO as solvent. To begin with on a smaller scale (50 mg scale), we had taken out sample from the reaction mixture at the end of 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 sec using a stopwatch in the initial phase and quenched the reaction in ice to confirm at which time reaction was completed. It was concluded that the reactions were completed in majority of the cases in just 30–40 sec. Further for consistency in results the reactions were scaled up to 100 mg and then to 1.0 g scale which has been reported. The results obtained were plotted, that is, time for completion of the reaction 30–180 sec versus polarity indices 3.1–7.2 for the same model reaction as shown in Figure
Time for completion of the reaction versus polar index.
Several phenacyl bromides consisting of both electron withdrawing and electron-donating groups reacted smoothly with thiourea or thioamide in DMSO as solvent to give 2-substitutedamino-4-aryl thiazoles in 91–96% yields within 30–40 sec under ambient reaction conditions. The results are summarized in Table
Synthesis of 2-substitued-amino-4-aryl thiazoles.
Ar | R | Thiazoles | Time (Sec.) | Yielda (%) |
---|---|---|---|---|
C6H5 | H | 30–40 | 96 | |
C6H5 | C6H5 | 30–40 | 93 | |
C6H5 | CH3 | 30–40 | 92 | |
C6H5 | CH2CH2C6H4 | 30–40 | 91 | |
C6H5 | 4-Cl C6H4 | 30–40 | 92 | |
C6H5 | 4-NO2 C6H4 | 30–40 | 92 | |
C6H5 | 4-F C6H4 | 30–40 | 93 | |
4-Cl C6H4 | H | 30–40 | 94 | |
4-Cl C6H4 | C6H5 | 30–40 | 93 | |
4-Cl C6H4 | CH3 | 30–40 | 91 | |
4-Cl C6H4 | 4-Cl C6H4 | 30–40 | 92 | |
4-Cl C6H4 | 4-NO2 C6H4 | 30–40 | 92 | |
4-Cl C6H4 | 4-F C6H4 | 30–40 | 94 | |
4-Br C6H4 | H | 30–40 | 95 | |
4-Br C6H4 | C6H5 | 30–40 | 92 | |
4-Br C6H4 | CH3 | 30–40 | 91 | |
4-Br C6H4 | 4-Cl C6H4 | 30–40 | 94 | |
4-Br C6H4 | 4- CH3C6H4 | 30–40 | 92 | |
4-Br C6H4 | 4-F C6H4 | 30–40 | 93 | |
4-CH3C6H4 | H | 180 | 93 | |
4-CH3C6H4 | C6H5 | 180 | 94 | |
4-CH3C6H4 | CH3 | 180 | 94 | |
4-CH3C6H4 | 4-CH3 C6H4 | 180 | 91 | |
4-CH3C6H4 | 4-Cl C6H4 | 180 | 93 | |
4-CH3C6H4 | 4-F C6H4 | 180 | 92 |
The above protocol was extended to synthesis of fanetizole
All the compounds were tested
Antibacterial activity of compounds with standard (diameter of the growth inhibition zone (Giz, mm) and minimal inhibitory concentration (MIC, mg/ml).
Strain | Compounds | |||||||||||
3e | 3k | 3m | 3q | 3s | Nitrofurantoin | |||||||
Giz | MIC's | Giz | MIC's | Giz | MIC's | Giz | MIC's | Giz | MIC's | Giz | MIC's | |
(mm) | ( | (mm) | ( | (mm) | ( | (mm) | ( | (mm) | ( | (mm) | ( | |
10 | 2 | 10 | 32 | 12 | 64 | 13 | 64 | 15 | 32 | 10 | 32 | |
10 | 4 | 13 | 2 | 10 | 32 | 10 | 64 | 12 | 32 | 11 | 32 | |
14 | 4 | 12 | 2 | 13 | 32 | 12 | 32 | 10 | 64 | 11 | 64 | |
13 | 4 | 12 | 2 | 14 | 16 | 14 | 64 | 11 | 64 | 13 | 64 |
Antifungal activity of compounds with standard (diameter of the growth inhibition zone (Giz, mm) and minimal inhibitory concentration (MIC, mg/ml)).
Strain | Compounds | |||||||||||
3e | 3k | 3m | 3q | 3s | Griseofulvin | |||||||
Giz | MIC's | Giz | MIC's | Giz | MIC's | Giz | MIC's | Giz | MIC's | Giz | MIC's | |
(mm) | ( | (mm) | ( | (mm) | ( | (mm) | ( | (mm) | ( | (mm) | ( | |
12 | 16 | 7 | 8 | 13 | 32 | 10 | 256 | 11 | 16 | 9 | 16 | |
11 | 64 | 8 | 64 | 11 | 64 | 10 | 128 | 12 | 256 | 8 | 32 | |
13 | 128 | 7 | 128 | 12 | 8 | 8 | 128 | 13 | 256 | 9 | 32 | |
10 | 8 | 6 | 32 | 11 | 128 | 7 | 32 | 13 | 8 | 9 | 64 |
Micro-organisms used in this study were as follows: gram-negative bacteria
Antimicrobial activity was examined by the disc diffusion method under standard conditions using Mueller-Hinton II agar medium (Becton Dickinson) for bacteria and Potato-dextrose agar for fungi (according to CLSI guidelines) [
In a typical reaction, a mixture of phenacyl bromide (1 gm, 3.6 mmol), thiourea (0.29 gm, 3.6 mmol) in 10 ml of DMSO was stirred at room temperature until completion of the reaction. The time of the reaction was monitored by a stopwatch. The progress of the reaction was monitored by thin-layer chromatography. On completion of the reaction, the reaction mixture was drowned into crushed ice. The precipitated product was filtered and dried. The product was pure enough (single spot on TLC) for all practical purposes. However, for characterization purposes, it was further purified by column chromatography. The yield of the dried product was found to be 0.96 g (96%).
In the parallel synthesizer wherein 10 samples can be stirred simultaneously, the products (
Characterization of representative compounds is given as below.
IR (KBr) 3433, 3019, 1602, 1531, 1519, 1482, 757 cm−1; 1
IR (KBr) 3404, 3019, 1601, 1599, 1541, 1498, 1311, 758 cm−1; 1
IR (KBr) 3196, 3016, 2975, 1602, 1584, 1552, 1495, 1463, 1335, 754 cm−1; 1
IR (KBr) 3335, 2923, 1588, 1520, 1495, 1482, 1399, 719 cm−1; 1
IR (KBr) 3383, 2934, 1597, 1524, 1552, 1492, 1398, 1338, 747 cm−1; 1
IR (KBr) 3437, 2923, 1614, 1570, 1534, 1501, 1381, 1333, 758 cm−1; 1
IR (KBr) 3244, 2923, 1604, 1519, 1504, 1458, 1437, 1317, 731 cm−1; 1
The authors are grateful to Professor M. N. Navale the founder president Sinhgad Technical Education Society, for providing them with the necessary financial support and infrastructure for carrying out this work.