A One-Pot Domino Synthesis of 4-(Trifluoromethyl)-2-thiazolamine

Abstract

Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is commonly used as an antibacterial agent in various industrial products and is often detected in wastewater effluent. Comparison was made for triclosan degradation by photolysis and TiO₂ photocatalysis (under UV irradiation (125 W)) based on analysis of transformation products, together with ecotoxicity evaluation. The morphology of the TiO₂ was characterized by X-ray diffractometry (XRD) and field emission gun-scanning electron microscopy (FEG-SEM). Triclosan quantitation was performed by high performance liquid chromatography (HPLC). The optimal condition was obtained using a response surface model and desirability profile. The initial concentration of triclosan used in all the experiments was 10 mg L^-1 to achieve comprehensive identification of transformation products. The optimal experimental condition was 30 mg L^-1 TiO₂ at pH 10. The photocatalytic system achieved > 99% triclosan degradation at 30 min of reaction. The mineralization rates by photolysis and photocatalysis were 25 and 90%, respectively. A total of 27 transformation products were identified using liquid chromatography quadrupole time of flight mass spectrometry (QTOF MS), being that 25 were new structures, not previously reported in the literature. Ecotoxicity assays demonstrated that triclosan and some of the major transformation products did not cause deleterious effects towards Lactuca sativa and Daphnia magna after 16 h of treatment.

Keywords:
4-(trifluoromethyl)-2-thiazolamine; one-pot; domino synthesis; nitrogen heterocycle

Introduction

In the field of medicinal chemistry, 2-aminothiazole plays an important role in drug design, and the incorporation of trifluoromethyl into 2-aminothiazole often enhances potent drugs’ bioavailability, reduces toxicity or improves affinity for the target receptor.¹,²,³,⁴ In general, fluoroalkyl-substituted 2-aminothiazoles are regarded as privileged structure motifs in medicinal chemistry due to its presence in antimicrobial or antiviral agents, anticancer agents, etc. (Figure 1).⁵,⁶,⁷,⁸

Figure 1
Examples of drug candidates with 5-(trifluoromethyl)-2-thiazolamine moiety.

5-(Trifluoromethyl)-2-thiazolamine is an important building block in various pharmaceutical and biologically-active compounds.⁹ Several synthetic methodologies are available for the synthesis of the 5-(trifluoromethyl)-2-thiazolamine. In general, fluoroalkyl-substituted 2-aminothiazoles are synthesized through condensation of thiourea with fluoroalkyl-substituted synthons¹⁰,¹¹,¹² or copper-mediated nucleophilic polyfluoroalkylation of halogen-substituted 2-amino-thiazoles.¹³,¹⁴ However, all of these methods suffer from drawbacks such as tedious procedures, low yields, requirements for excess reagents or catalysts and difficult workup procedures. 5-(Trifluoromethyl)-2-thiazolamine has also been prepared by the reaction of 2-aminothiazoles with CF₃I (or CF₃Br), but this is expensive and requires harsh conditions: (i) low temperature (–78 °C), (ii) a large amount of solvent and (iii) special apparatus.¹⁵,¹⁶,¹⁷

In our previous unpublished work,, we attempted to prepare 5-(difluoromethyl)-2-thiazolamine via reaction of 2-thiazolamine with CHF₂Cl, which led to N-alkylated product quantitatively. The N-alkylated product could also be obtained even using 2-thiazolamine amino-protected with acetyl or Boc. So we did not adopt the reaction between 2-aminothiazoles and CF₃I to prepare 5-(trifluoromethyl)-2-thiazolamine.

Herein we report a new method for the synthesis of 5-(trifluoromethyl)-2-thiazolamine (1) from 3-bromo-1,1,1-trifluoro-2-propanone (2) in one-pot procedure. Commercially available 2 reacted with phosphorus pentasulfide to yield the key intermediate 3-bromo-1,1,1-trifluoropropane-2-thione (3). Then cyanamide was added and the cyclization reaction furnished 1 on a multi-gram scale with acceptable yield (Scheme 1).

Scheme 1
The synthesis of 5-(trifluoromethyl)-2-thiazolamine.

Results and Discussion

Initially, the reaction between 3-bromo-1,1,1-trifluoro-2-propanone (1.0 equiv), different amounts of phosphorus pentasulfide, and then cyanamide (1.0 equiv), in the presence of AcONa (1.0 equiv), was used as a model reaction to optimize the thionation conditions. The thionation reaction was performed at 30 °C and the cyclization took place at 60 °C for 30 h, then product 1 was isolated by column chromatography on silica gel and its structure was confirmed by ¹H nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS). Results are summarized in Table 1.

Table 1
Optimization of the thionation conditions

entry	P2S5 / equiv	Additive	Solvent	Thionation time / h	Yielda / %
1	1.5	–	THF	14	30
2	1.0	–	THF	14	39
3	0.6	–	THF	14	45
4	0.4	–	THF	14	37
5	0.6	–	THF	10	41
6	0.6	–	THF	18	43
7	0.6	NaHCO3	THF	14	44
8	0.4	NaHCO3	THF	14	38
9	0.6	NaHCO3	THF	10	42
10	0.6	–	DMF	14	–
11	0.6	–	CH3CN	14	36
12	0.6	–	MTBE	14	31
13	0.6	–	toluene	14	4
14	0.6	–	CHCl3	14	5

• ^a
  Isolated yield of 5-(trifluoromethyl)-2-thiazolamine.

As shown in Table 1, the amount of phosphorus pentasulfide had a significant influence on the yields of target compound, 0.6 equiv of phosphorus pentasulfide gave the highest yield up to 45% (entries 1-4). From 10 h or 18 h reaction, a small decrease in product yield occurred, which may be due to the incompletion of the reaction and the degradation of the product, respectively (entries 5-6). Encouraged by Scheeren’s report¹⁸ on the sulfurization of carbonyl groups in the presence of sodium hydrogen carbonate (NaHCO₃) as an activator, we tested this in several experiments, but the addition of sodium hydrogen carbonate (6 equiv) did not accelerate the transformation nor reduce the requirement of phosphorus pentasulfide (entries 7-9). We also investigated the influence of solvents (entries 10-14). Nonpolar solvent (toluene or chloroform) provided poor yields of 5-(trifluoromethyl)-2-thiazolamine (1), and the reaction in dimethylformamide (DMF) did not present the formation of product probably due to the reaction between DMF and phosphorus pentasulfide. In tetrahydrofuran (THF), an acceptable yield was obtained (45%). These results proved that THF is a good solvent for the reaction.

With the optimized reaction conditions in hand for thionation reaction, cyclization conditions were optimized by using 1.0 equiv of cyanamide (Table 2). The reaction with increased amounts of NaOAc afforded higher yields, and in the absence of base, the reaction did not take place (entries 1-5). When the reaction temperature was changed to 30 or 45 °C, the yields of product diminished to 25 and 44%, respectively (entries 6-7). Meanwhile, we investigated the influence of the reaction time: by shortening the time, a slight increase was obtained (entries 8-9). In addition, the results demonstrate that other bases such as t-BuOK and n-BuLi can afford similar yields (entries 3, 10-12). While considering the safety and simplicity of operation, sodium acetate and potassium t-butoxide are better choices for this reaction.

Table 2
Optimization of the cyclization conditions

entry	Base / equiv	Temperature / °C	Cyclization time / h	Yielda / %
1	AcONa(0.5)	60	30	24
2	AcONa(1.0)	60	30	45
3	AcONa(1.5)	60	30	53
4	AcONa(2.0)	60	30	55
5	–	60	30	–
6	AcONa(1.5)	30	30	25
7	AcONa(1.5)	45	30	44
8	AcONa(1.5)	60	25	56
9	AcONa(1.5)	60	40	51
10	t-BuOK(1.5)	60	25	54
11	t-BuOK(1.5)	25	30	49
12	n-BuLi(1.5)	-78 - 0	22	53

• ^a
  Isolated yield of 5-(trifluoromethyl)-2-thiazolamine.

A plausible mechanism for cyclization reaction is shown in Scheme 2. Cyanamide 4 deprotonates into its anion 5 via hydrogen abstraction reaction by the base. Successively, a nucleophilic substitution reaction with 3 gives carbodiimide intermediate 6, which becomes prone to attack due to ketoenol tautomerism forming tautomer 7 and the attack takes place on the carbon of the carbodiimide producing anion 8. Finally, compound 8 abstracts a hydrogen from conjugate acid to furnish the desired compound 5-(trifluoromethyl)-2-thiazolamine (1) and regenerate the base.

Scheme 2
The possible mechanism of cyclization reaction.

Conclusions

We have developed a novel, mild, efficient method for the preparation of 5-(trifluoromethyl)-2-thiazolamine. Significant advantages of this method include simple and readily available precursors, easy workup, and acceptable yield.

Additions and Corrections

• Title:
  Where it reads 5-(Trifluoromethyl)-2-thiazolamine
  Should be read 4-(trifluoromethyl)-2-thiazolamine
  Abstract:
  Where it reads 5-(Trifluoromethyl)-2-thiazolamine
  Should be read 4-(trifluoromethyl)-2-thiazolamine
  Keywords:
  Where it reads 5-(trifluoromethyl)-2-thiazolamine
  Should be read 4-(trifluoromethyl)-2-thiazolamine
  Scheme 1:
  Where it reads The synthesis of 5-(trifluoromethyl)-2-thiazolamine.
  

  
  
  Should be read The synthesis of 4-(trifluoromethyl)-2-thiazolamine.
  

  
  
  Introduction:
  Where it reads 5-(trifluoromethyl)-2-thiazolamine
  Should be read 4-(trifluoromethyl)-2-thiazolamine
  Tables 1 and 2:
  Where it reads aIsolated yield of 5-(trifluoromethyl)-2-thiazolamine.
  Should be read aIsolated yield of 4-(trifluoromethyl)-2-thiazolamine
  Scheme 2:
  Where it reads
  

  
  
  Should be read
  

  
  
  Page 2390: Where it reads
  A plausible mechanism for cyclization reaction is shown in Scheme 2. Cyanamide 4 deprotonates into its anion 5 via hydrogen abstraction reaction by the base. Successively, a nucleophilic substitution reaction with 3 gives carbodiimide intermediate 6, which becomes prone to attack due to keto-enol tautomerism forming tautomer 7 and the attack takes place on the carbon of the carbodiimide producing anion 8. Finally, compound 8 abstracts a hydrogen from conjugate acid to furnish the desired compound 5-(trifluoromethyl)-2-thiazolamine (1) and regenerate the base.
  Should be read
  A plausible mechanism for cyclization reaction is shown in Scheme 2. 3-Bromo-1,1,1-trifluoropropane-2-thione 3 deprotonates and then offered the intermediate 5 via a process similar to Hoffmann rearrangement. Successively, intermediate 5 is added with cyanamide after deprotonation to form intermediate 6. Then the intermediate 7 is obtained by intramolecular cyclization. Finally, 7 abstracts a hydrogen from conjugate acid to furnish the desired compound 4-(trifluoromethyl)-2-thiazolamine 1 and regenerate the base.
  Conclusions:
  Where it reads 5-(trifluoromethyl)-2-thiazolamine
  Should be read 4-(trifluoromethyl)-2-thiazolamine

Acknowledgments

The authors gratefully acknowledge financial support from the Discipline Construction Program of Shenyang Pharmaceutical University (No. 52134606).

Supplementary Information

Additional spectroscopic data are available free of charge at http://jbcs.sbq.org.br.

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Publication Dates

• Publication in this collection
  01 Dec 2016
• Date of issue
  2016

History

• Received
  12 Feb 2016
• Accepted
  03 May 2016