Considering the various applications of thioamides, we investigate various synthetic novel protocols for their synthesis such as citric acid method, BF3-etherate method, Dowex-DR-2030 and Amberlyst-15 methods. These methods are discussed follow:
Citric acid Method: Pyrazole carbonitrile 1 (1mmol) and citric acid (10 mol %) was dissolved in 5 ml ethanol and mixture was heated at 700C. To this reaction mass MgCl2 (0.5 mmol) was added followed by lot wise addition of thioacetamide (1.5mmol). The heating was continued for next 2 hr. On completion of reaction the mass was poured in warm water and the solid obtained was filter and recrystallized to obtained pure product.
BF3-Etherate method: Mixture of Compound 1 (1mmol), ethanol 5 mL and BF3-Etherate (10 mol %) heated up to 700C and then thioacetamide (1.5mmol) was added and heating was continued for next 1-2 hrs at same temperature. Reaction mass poured in luke warm water. Crude solid obtained was filtered, dried and recrystallized with aqueous ethanol.
Dowex DR-2030 method: Mixture of Compound 1 (1mmol), MgCl2 (0.5 mmol), Dowex DR- 2030 (10 mol %) was dissolve in ethanol 5 mL and reaction mass heated up to 70oC. To the reaction mixture thioacetamide (1.5mmol) was added dropwise and heating was continued for further 6 hrs. Reaction was monitored by TLC. Reaction mixture was filtered under hot condition and filtrate was poured in water. The obtained crude solid was filtered, dried and recrystallized from solvent. Separated Dowex-DR was reused for further reactions.
Amberlyst-15 method: Amberlyst-15 (10 mol%) was added in the solution of pyrazole carbonitrile (1mmol) in ethanol (5ml). The reaction was heated at 700C. Then thioacetamide (1mmol) was added dropwise and the reaction mass was further heated at 700C for 60 minutes. The progress of reaction was monitor by TLC and the mixture was filter in hot condition and mother liquor was poured in water. Obtained solid was filtered, wash with cold water and crystallized in ethanol to obtained pure product. Residual Amberlyst-15 was reused for next cycle.
Catalysts optimized for the pyrazole thioamide process and results are summarized in above Table 1. Reaction could be efficiently completed in all these mol % like 5 mol %, 10 mol %, 15 mol% and 20 mol % catalysts but Amberlyst-15 was found to be an efficient and recyclable catalyst for this transformation. This method requires only stoichiometric amount of 10 mol % Amberlyst-15 in ethanol as a solvent to obtain excellent yield of 3-Aryl-1-phenyl-1H-pyrazole-4-carbothioamides (97-99%).
Table 1 – Optimization of catalyst for the synthesis of pyrazole thioamide a
Entry
|
Catalysts
|
Yield (%)b
|
Time (hrs)
|
5 mol % catalyst
|
10 mol % catalyst
|
15 mol % catalyst
|
20 mol % catalyst
|
1
|
Citric acid
|
77
|
91
|
75
|
68
|
2
|
2
|
BF3-Etherate
|
87
|
73
|
73
|
70
|
1-2
|
3
|
Dowex DR-2030
|
52
|
50
|
69
|
61
|
6
|
4
|
Amberlyst-15
|
65
|
97-99
|
53
|
50
|
1
|
a) Experimental conditions: Pyrazole-4-nitrile (1mmol), Thioacetamide (1 mmol), ethanol 5ml at 700C
b) Isolated yield.
Thionation reagent (thioacetamide) optimized for the Amberlyst-15 catalyst and results are summarized in Table 2. Reaction could be efficiently completed in all these mmol like 1.0, 1.2, 1.3, 1.4, 1.5, 2.0, and 2.6 mmol reagent. but 1.0 mmol of thioacetamide was found to be an efficient for this transformation. This method requires only stoichiometric amount of 1 mmol of thioacetamide in ethanol as a solvent to obtain excellent yield of 3-Aryl-1-phenyl-1H-pyrazole-4-carbothioamides (97-99%).
Table 2– Optimization of reagent for the synthesis of pyrazole thioamide a
Entry
|
Reagent (Thioacetamide)
In mmol
|
Time (hrs)
|
Yield (%)b
|
1
|
2.0
|
7
|
90
|
2
|
1.2
|
9
|
85
|
3
|
1.3
|
7
|
95
|
4
|
1.5
|
12
|
88
|
5
6
7
|
1.0
1.4
2.6
|
1
6
7
|
97-99
91
92
|
a) Experimental conditions: Pyrazole-4-nitrile (1mmol), Amberlyst-15 10 mol % in ethanol at 700C
b) Isolated yield.
Similarly, optimization of solvent was investigated such as DMF, ethanol, acetonitrile, PEG 200, methanol, water etc. In DMF, acetonitrile, PEG 200 and methanol less yield was obtained. In water in sticky reaction mass was obtained. (Table 3). It was found that 10 mol % Amberlyst catalyst and 1 mmol of thioacetamide efficiently completed the reaction within 1 hrs with maximum yield in ethanol as a medium.
Table 3 - Solvent optimization for one-pot synthesis of pyrazole thioamide a
Entry
|
Amberlyst-15
mol %
|
Solventa
|
Condition
|
Time (hrs)
|
Yield (%)b
|
-
|
10 %
|
DMF
|
50°C
|
12
|
65
|
-
|
10 %
|
Ethanol
|
70°C
|
1
|
97-99
|
-
|
10 %
|
Acetonitrile
|
50°C
|
6
|
53
|
-
|
10 %
|
PEG 200
|
52°C
|
8
|
50
|
-
|
10 %
|
Methanol
|
50°C
|
6
|
77
|
-
|
10 %
|
Water
|
52°C
|
24
|
Sticky mass
|
a) Experimental conditions: Pyrazole nitrile(1mmol),Thioacetamide (1.1 mmol),Magnesium Chloride (0.5mmol).
b) Isolated yieldb.
Hence 10 mol% Amberlyst-15 and 1 equivalent thioacetamide in ethanol as a best choice for the synthesis of 3-Aryl-1-phenyl-1H-pyrazole-4-carbothioamides. To generalized the scope of this protocol variety of pyrazol-4-carbonitriles were selected for the synthesis of novel corresponding 3-Aryl-1-phenyl-1H-pyrazole-4-carbothioamides.
The appealing thing of this method is that the reaction rate is rapid and product obtained with high purity and no need of column chromatography. To check the generality and scope of the optimized reaction, the methodology was evaluated by employing different substituted 3-Aryl-1-phenyl-1H-pyrazole -4-carbonitrile (1a), thioacetamide (2a) (1 mmol) and amberlyst-15 (Scheme 1). The 3-Aryl-1-phenyl-1H-pyrazole-4-carbonitrile having electron withdrawing and donating group participated well in this reaction.
The resultant 1,3-diphenyl-1H-pyrazole-4-carbothioamide (3a-j) was obtained in excellent yields as summarized in Table 4.