# Regioselective Thiocyanation of Aromatic and Heteroaromatic Compounds by Using Boron Sulfonic Acid as a New, Efficient, and Cheap Catalyst in Water

Authors: Sami Sajjadifar; Omid Louie
Journal: Journal of Chemistry
 (2013)

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## Abstract

Highly efficient regioselective thiocyanations of indoles andN,N-disubstituted anilines are achieved via a green and simple protocol using boron sulfonic acid (BSA) as a new catalyst and KSCN/H2O2 as a mild and environmentally friendly oxidant in aqueous media.


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## Body

## 1. Introduction

The electrophilic thiocyanation of aromatics and heteroaromatics is an important carbon-heteroatom bond formation reaction in organic synthesis [1–3]. Thiocyanate is a versatile synthon which can be readily transferred to other functional groups such as sulfide [4–7], aryl nitrile [8], thiocarbamate [9], and thionitrile [10]. Therefore, it is important to find the new and fast methods for synthesis of thiocyanate group containing aromatic systems [11]. In view of the versatility of thiocyanate group in heterocyclic construction [3], it will be important to probe the thiocyanation of aromatic and heteroaromatic compounds. Several methods have been developed for the thiocyanation of arenes by using various reagents under certain conditions [12–21]. Yet, only a limited number of reagents, such as bromine/potassium thiocyanate (only for indoles) [18], N-thiocyanatosuccinimide (only for 5-methoxy-2-methylindole and accompanied by two bisthiocyanates) [19], ceric ammonium nitrate (CAN) [20], acidic mont K10 clay [21], iodine/methanol, oxone [22], diethyl azodicarboxylate [23], IL-OPPh2 [24], potassium peroxydisulfate-copper(II) [25], and HCl/H2O2 [26] have been applied to the thiocyanation of aromatic and heteroaromatic systems. However, these methodologies suffer from one or more drawbacks such as the low availability or hard preparation of starting materials [18, 19], the requirement of large excess of strong oxidizing reagents, low yields for some compounds [20], and performances under certain special conditions [21]. Hence, a requirement for developing alternative synthesis routines accessible to the thiocyanation of aromatic and heteroaromatic compounds is in high demand.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 [27–29]. Therefore, the development of an efficient and convenient thiocyanation synthetic methodology in aqueous medium is an important research area [30, 31].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 (Scheme1) [32].Scheme 1
Boron sulfonic acid synthesis under nitrogen atmosphere at room temperature.


## 2. Experimental

### 2.1. General

Chemicals were purchased from Merck chemical company. IR spectra of the compounds were obtained on a Shimadzu IR-435 spectrometer using a KBr disk. The1H NMR spectra were recorded on a Bruker AQS 300 Avance instrument at 300 MHz in dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as an internal standard. The progress of reaction was followed with TLC using silica gel SILG/UV 254 and 365 plates. All products are known compounds and were characterized by comparing the IR, 1H, and 13C NMR spectroscopic data, and their melting points with the literature values. All yields refer to isolated products.


#### 2.1.1. Typical Procedure for 3-Thiocyanato Indole Synthesis

A suspension of indole1a(0.117 g, 1 mmol), potassium thiocyanate (0.294 g, 3 mmol), and BSA/SiO2 (0.05 g, 5%) in H2O (7–10 mL) was stirred at room temperature for 5–10 min. After that period H2O2 (30%, 0.45 mL) was dropwisely added (2–5 min). The progress of the reaction was monitored by TLC (ethyl acetate: n-hexane, 1 : 10). After completion of the reaction, the reaction mixture was extracted with CHCl3 (3 × 20 mL), dried with Na2SO4 (5 g) for 20 min, filtered, and chloroform removed. Yield 0.167 g (96%); dark brown solid; mp 71–73°C (1b) [2, 22, 33]. FT-IR (KBr,): υ (cm−1) 2159, 3289; 1H NMR (FT-300 MHz, CDCl3): δ (ppm) 8.87 (1H, br s, NH), 7.83 (1H, d, J=8.8 Hz), 7.46–7.23 (4H, m); 13C NMR (75 MHz, CDCl3): δ (ppm) 136.06, 131.22, 127.66, 123.83, 121.87, 118.65, 112.24, and 91.76.


#### 2.1.2. Preparation of Boron Sulfonic Acid (BSA) [26, 32]

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-d6 showed absorption at 12.22 ppm) and then 14.4 g SiO2 was added and mixed. Finally, dried and a grayish solid material was obtained in 95.6% yield (21.6 g).


## 2.1. General

Chemicals were purchased from Merck chemical company. IR spectra of the compounds were obtained on a Shimadzu IR-435 spectrometer using a KBr disk. The1H NMR spectra were recorded on a Bruker AQS 300 Avance instrument at 300 MHz in dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as an internal standard. The progress of reaction was followed with TLC using silica gel SILG/UV 254 and 365 plates. All products are known compounds and were characterized by comparing the IR, 1H, and 13C NMR spectroscopic data, and their melting points with the literature values. All yields refer to isolated products.


### 2.1.1. Typical Procedure for 3-Thiocyanato Indole Synthesis

A suspension of indole1a(0.117 g, 1 mmol), potassium thiocyanate (0.294 g, 3 mmol), and BSA/SiO2 (0.05 g, 5%) in H2O (7–10 mL) was stirred at room temperature for 5–10 min. After that period H2O2 (30%, 0.45 mL) was dropwisely added (2–5 min). The progress of the reaction was monitored by TLC (ethyl acetate: n-hexane, 1 : 10). After completion of the reaction, the reaction mixture was extracted with CHCl3 (3 × 20 mL), dried with Na2SO4 (5 g) for 20 min, filtered, and chloroform removed. Yield 0.167 g (96%); dark brown solid; mp 71–73°C (1b) [2, 22, 33]. FT-IR (KBr,): υ (cm−1) 2159, 3289; 1H NMR (FT-300 MHz, CDCl3): δ (ppm) 8.87 (1H, br s, NH), 7.83 (1H, d, J=8.8 Hz), 7.46–7.23 (4H, m); 13C NMR (75 MHz, CDCl3): δ (ppm) 136.06, 131.22, 127.66, 123.83, 121.87, 118.65, 112.24, and 91.76.


### 2.1.2. Preparation of Boron Sulfonic Acid (BSA) [26, 32]

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-d6 showed absorption at 12.22 ppm) and then 14.4 g SiO2 was added and mixed. Finally, dried and a grayish solid material was obtained in 95.6% yield (21.6 g).


## 2.1.1. Typical Procedure for 3-Thiocyanato Indole Synthesis

A suspension of indole1a(0.117 g, 1 mmol), potassium thiocyanate (0.294 g, 3 mmol), and BSA/SiO2 (0.05 g, 5%) in H2O (7–10 mL) was stirred at room temperature for 5–10 min. After that period H2O2 (30%, 0.45 mL) was dropwisely added (2–5 min). The progress of the reaction was monitored by TLC (ethyl acetate: n-hexane, 1 : 10). After completion of the reaction, the reaction mixture was extracted with CHCl3 (3 × 20 mL), dried with Na2SO4 (5 g) for 20 min, filtered, and chloroform removed. Yield 0.167 g (96%); dark brown solid; mp 71–73°C (1b) [2, 22, 33]. FT-IR (KBr,): υ (cm−1) 2159, 3289; 1H NMR (FT-300 MHz, CDCl3): δ (ppm) 8.87 (1H, br s, NH), 7.83 (1H, d, J=8.8 Hz), 7.46–7.23 (4H, m); 13C NMR (75 MHz, CDCl3): δ (ppm) 136.06, 131.22, 127.66, 123.83, 121.87, 118.65, 112.24, and 91.76.


## 2.1.2. Preparation of Boron Sulfonic Acid (BSA) [26, 32]

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-d6 showed absorption at 12.22 ppm) and then 14.4 g SiO2 was added and mixed. Finally, dried and a grayish solid material was obtained in 95.6% yield (21.6 g).


## 3. Results and Discussion

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 2). To identify optimal conditions for the synthesis of aryl thiocyanates, we began with an investigation of the conversion of indole into the corresponding indole thiocyanate using BSA/H2O2/KSCN in water as a model reaction (Scheme 2).Scheme 2
The solvent effect on product yields was investigated using1a as a substrate. Both the yields and reaction times listed in Table 1 suggest that water appears to be very favorable for thiocyanations in presence of BSA (as a strong and new catalyst).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 (Table2).Table 1
Solvent effects on the thiocyanation of1a.
SolventTime (h, min)aYield (%)bWater00:0598Acetonitrile01:2080Tetrahydrofuran02:0073Dichloromethane08:0070Carbon tetrachloride12:0047Ethanol00:3089aThe reaction time.bIsolated yield of the products after column chromatography.Table 2
Substrate scope in the thiocyanation reaction of arenes using KSCN/BSA/H2O2 [26].
EntrySubstrate (a)Product (b)Time (min)Yield %15982158931382425945109864080730788109791495101092118055a127060a136045a1415161718192021aThis reactions were not complete (determined by TLC).As shown in Table2, indole and electron-rich indoles gave the desired products in excellent yields (Table 2, entries 1–3). Also, electron-deficient indoles such as 5-bromoindole reacted with potassium thiocyanate and BSA/H2O2 to afford the corresponding 5-bromo-3-thiocyanatoindole in good yield, but required longer reaction time (Table 2, entry 4). This observation can be attributed to the lower electron density of such substrates. The lower yield is probably attributed to the steric hindrance of 2-substituted indole (Table 2, entry 3). The addition was highly regioselective occurring at the 3-position of the indole ring [25].Various N,N-disubstituted aromatic amines were converted into the respective 4-thiocyanato amines in high to excellent overall yields (Table 2, entries 5–10). The reactions were clean and the products were obtained with high-paraselectivity (Table 2, entries 9, 10). However, in the case of parasubstituted amine, ortho-thiocyanation did not occur (Table 2, entry 14).When indoline was used as a substrate, the reaction was not complete (Table2, entry 11). The same result was shown for 1,2,3,4-tetrahydroquinoline (Table 2, entry 12) and 1-phenylpiperazine (Table 2, entry 13). On the other hand, N,N-4-trimethylaniline, o-methylaniline, anisole, pyrrole, acetanilide, imidazole, pyrazine, and pyrrole-3-carbaldehyde (Table 2, entries 14–21) did not react with potassium thiocyanate and BSA/H2O2 to afford the corresponding derivatives.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 Scheme3. In the first step, H2O2 reacts with BSA(H+) to presumably in situ form hydrogen peroxonium ion (H3O2+) [34]. We have shown that the counter ion of an acid did not have any role in the course of the reaction and H2SO4 acts the same as HCl. Subsequently, reaction of hydrogen peroxonium ion with SCN− generates HOSCN, which is in the presence of H+ able to produce thiocyanium ion +SCN35 and H2O. In the last step of the reaction electrophilic substitution of thiocyanium ion +SCN with indole will generate the corresponding indole thiocyanate.Scheme 3
The proposed mechanism for the thiocyanation of indoles andN,N-dialkylanilines.


## 4. Conclusions

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.



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*Source: 674946-2012-08-15.xml*