Highly efficient regioselective thiocyanations of indoles and
The electrophilic thiocyanation of aromatics and heteroaromatics is an important carbon-heteroatom bond formation reaction in organic synthesis [
There is an increasing interest in the use of environmentally benign reagents and procedures. Aqueous mediated reactions have received considerable attention in organic synthesis due to the environmentally safety reasons. Water is a desirable solvent for chemical reactions because it is safe, nontoxic, environmentally friendly, readily available, and inexpensive compared to organic solvents [
Boron sulfonic acid (BSA) as acidic catalyst was introduced by Kiasat and Fallah-Mehrjardi and used for the regioselective conversion of epoxides to thiocyanohydrins under solvent-free reaction conditions (Scheme
Boron sulfonic acid synthesis under nitrogen atmosphere at room temperature.
Chemicals were purchased from Merck chemical company. IR spectra of the compounds were obtained on a Shimadzu IR-435 spectrometer using a KBr disk. The 1H NMR spectra were recorded on a Bruker AQS 300 Avance instrument at 300 MHz in dimethyl sulfoxide (DMSO-
A suspension of indole
A 50 mL suction flask was equipped with a constant pressure dropping funnel. The gas outlet was connected to a vacuum system through an adsorbing solution (water) and an alkali trap. Boric acid (1.55 g, 25 mmol) was charged in the flask and chlorosulfonic acid (8.74 g, ca. 5 mL, 75 mmol in 5 mL CH2Cl2) was added dropwise over a period of 1 h at room temperature under N2 gas. HCl evolved immediately. After completion of the addition, the mixture was shaken for 85 min, while the residual HCl was eliminated by suction. The mixture was washed with diethyl ether to remove the unreacted chlorosulfonic acid (1H NMR spectrum of BSA in acetone-
The thiocyanation was investigated at various conditions. In the absence of BSA, reaction was not accomplished, but in the presence of 5% BSA (0.05 g BSA equal 0.15 mmol H+) the reaction took place with best result. We have found that BSA is active as a catalyst towards the thiocyanation of aromatic and heteroaromatic compounds using H2O2 as an oxidant (Scheme
The solvent effect on product yields was investigated using
The stoichiometry of the reactants was also varied. A ratio of 1 : 4 : 3 (indole : H2O2 : KSCN) was found to be the most suitable, and decreasing the amount of H2O2 or potassium thiocyanate increased the reaction time and lowered the yield.
The scope of this reaction was further examined using various arenes under optimized conditions (Table
Solvent effects on the thiocyanation of
Solvent | Time (h, min)a | Yield (%)b |
---|---|---|
Water | 00:05 | 98 |
Acetonitrile | 01:20 | 80 |
Tetrahydrofuran | 02:00 | 73 |
Dichloromethane | 08:00 | 70 |
Carbon tetrachloride | 12:00 | 47 |
Ethanol | 00:30 | 89 |
aThe reaction time.
bIsolated yield of the products after column chromatography.
Substrate scope in the thiocyanation reaction of arenes using KSCN/BSA/H2O2 [
Entry | Substrate (a) | Product (b) | Time (min) | Yield % | |
---|---|---|---|---|---|
1 | 5 | 98 | |||
2 | 15 | 89 | |||
3 | 13 | 82 | |||
4 | 25 | 94 | |||
5 | 10 | 98 | |||
6 | 40 | 80 | |||
7 | 30 | 78 | |||
8 | 10 | 97 | |||
9 | 14 | 95 | |||
10 | 10 | 92 | |||
11 | 80 | 55a | |||
12 | 70 | 60a | |||
13 | 60 | 45a | |||
14 | 15 | 17 | 18 | 20 | 21 |
aThis reactions were not complete (determined by TLC).
As shown in Table
When indoline was used as a substrate, the reaction was not complete (Table
In comparison with other reported methods using other reagents which require refluxing conditions, the assistance of ultrasonic irradiation, toxic solvent, or oxidant, this method works under milder and greener reaction conditions.
The proposed reaction mechanism is shown in Scheme
The proposed mechanism for the thiocyanation of indoles and
We have developed an efficient, simple, and green thiocyanation of aromatic and heteroaromatic compounds using BSA/H2O2/KSCN in water as solvent, which takes place with high regioselectivity. This procedure offers advantages such as simple workup, short reaction time, low cost of reagents, mild reaction conditions, and clean formation of the desired products in high yields.
The authors gratefully acknowledge partial support of this work by Payame Noor University (PNU) of Ilam. They thank Professor Dr. Marijan Kočevar (Faculty of Chemistry and Chemical Technology, University of Ljubljana) for the very helpful comments on this paper.