Citric acid as a trifunctional organocatalyst for thiocyanation of aromatic and heteroaromatic compounds in aqueous media

Article abstract of DOI:10.1139/v2012-013

A green and simple procedure for the thiocynation of aromatic and heteroaromatic rings in the presence of a catalytic amount of citric acid in water are described. The reactions proceed in high yields, with short reaction times and under mild conditions.

Full text of DOI:10.1139/v2012-013

427
Citric acid as a trifunctional organocatalyst for
thiocyanation of aromatic and heteroaromatic
compounds in aqueous media
Ardeshir Khazaei, Mohammad Ali Zolfigol, Mohmmad Mokhlesi, and
Mahtab Pirveysian
Abstract: A green and simple procedure for the thiocynation of aromatic and heteroaromatic rings in the presence of a cata-
lytic amount of citric acid in water are described. The reactions proceed in high yields, with short reaction times and under
mild conditions.
Key words: thiocyanation, citrc acid, organocatalyst, hydrogen peroxide, water.
Résumé : On a mis au point une méthode simple et écologique d’effectuer la thiocyanuration de noyaux aromatiques et hé-
téroaromatiques, en présence d’une quantité catalytique d’acide citrique, dans l’eau. Les réactions se font dans des condi-
tions douces, de courts temps de réaction et avec des rendements élevés.
Mots‐clés : thiocyanuration, acide citrique, catalyseur organique, peroxyde d’hydrogène, eau.
[Traduit par la Rédaction]
chemistry.31 For example, the thiocyanato group occurs as an
Introduction
important functionality in certain anticancer natural products
formed by deglycosylation of glucosinolates derived from
cruciferous vegetables.32–36 On the other hand, thiocyano-
substituted compounds are a useful precursor for the synthe-
sis of organosulfur compounds, in which the thiocyanate
group will be readily transferred to other functional groups
such as sulfide,35 aryl nitrile,36 thiocarbamate,37 and thioni-
trile.38 Several methods have been developed for the thiocya-
nation of arenes by using various reagents39–41 such as N-
thiocyanatosuccinimide,42 ceric ammonium nitrate (CAN),43
acidic mont K10 clay,44 iodine/methanol,45 diethyl azodicar-
Organocatalysis has emerged during the last decade as one
of the major issues in the development of catalytic chemical
technology.1 As for conventional catalysis with transition-
metal complexes, by using organic catalysts large quantities
of products are expected to be prepared using a minimal
amount of small organic molecules.2 The recent organocata-
lytic protocols are particularly attractive because of the mild-
ness of the reaction conditions, operational simplicity, the
potential for the development of large scale production, and
the ready availability and low toxicity of the organocata-
lysts.3–12 A diverse set of organocatalytic reactions, including
C–C, C–N, and C–O bond formation,13 Diels–Alder,14,15
Baylis–Hilman,16,17 Mannich,14,18–20 Michael,14,21,22 Friedel–
Crafts alkylation,23 oxidation,24,25 and carbohydrate synthe-
sis,26 has benefited from the developments in this area.27–29
On the other hand, organocatalyzed reactions using water as
a solvent have attracted a great deal of attention mainly be-
cause of the low cost, the safety, and the environmentally be-
nign nature of water. The synthesis of organic molecules via
reactions in water is an extensively investigated topic, which
entails the additional challenge of water tolerance for a cata-
lyst. Thus, the development of small organic molecules that
catalyze reactions in water is currently an important goal
amongst today’s synthetic community.30
boxylate,46 IL-OPPh2,47 pentavalent iodine,48 IBX,49 FeCl3,
50
potassium peroxydizulfate – copper(II),51 and Selectfluor.52
However, most of the reported methods for the synthesis of
aryl thiocyanates are associated with one or more of the fol-
lowing drawbacks such as low yields, long reaction times, the
use of large amounts of catalyst, and the use of toxic or ex-
pensive catalysts. Thus, the search for finding an efficient, in-
expensive, and nonpolluting method for the synthesis of this
class of compounds is still of practical importance.
Because of these problems and the recent intense attention
on environmentally benign protocols, the search for new and
efficient catalysts that are able to promote organic reactions
under green conditions is of interest for the production of
aryl thiocyanates. In this regard, we report the synthesis of
organo thiocyanate derivatives in the presence of a catalytic
amount of citric acid in aqueous media.
The thiocyanation reaction is one of the most useful carbon–
sulfur bond-forming reactions. Thiocyanates have gained
considerable importance in various areas of organosulfur
Received 21 September 2011. Accepted 23 November 2011. Published at www.nrcresearchpress.com/cjc on 4 April 2012.
A. Khazaei, M.A. Zolfigol, M. Mokhlesi, and M. Pirveysian. Faculty of Chemistry, Bu-Ali Sina University, P.O. Box 6517838683,
Hamedan, Iran.
Corresponding author: Ardeshir Khazaei (e-mail: akhazaei_1326@yahoo.com).
Can. J. Chem. 90: 427–432 (2012)
doi:10.1139/V2012-013
Published by NRC Research Press

428
Can. J. Chem. Vol. 90, 2012
Scheme 1. Thiocyanation of indole in the presence of citric acid.
SCN
Results and discussion
For the synthesis of aryl thiocyanate, conversion of indole
into its corresponding indole thiocyanate in water and room
temperature has been considered as a model reaction
(Scheme 1).
Cat. (10% mol)/ KSCN
H2O2 30%/ H2O/rt
N
N
H
H
20 min
In an initial experiment, we examined the reaction of in-
dole and KSCN in aqueous media by using different catalysts
such as sodium citrate, benzenesulfonic acid, 1-(phenylthio)
acetic acid, 4-chlorobenzoic acid, 4-methoxybenzoic acid,
and citric acid. The results are summarized in Table 1. As
Table 1 indicates, higher yield and shorter reaction times
were obtained when citric acid was utilized as the catalyst.
Brønsted acid organocatalysts such as benzenesulfonic acid,
1-(phenylthio)acetic acid, 4-chlorobenzoic acid, and 4-
methoxybenzoic acid gave low yields of the corresponding
3-thiocyanato indole. The use of sodium citrate was also ex-
amined and a moderate yield of product was obtained. Cit-
ric acid very efficiently gave an excellent yield of the
corresponding 3-thiocyanato indole in a shorter reaction
time. This might be due to the solubility of citric acid in
water, which could accelerate the reaction rate.
91%
COOH
COOH
COOH
HO
Cat.
Table 1. Thiocyanation of indole using different catalysts
(10 mol %).
Yield
Time (h) (%)
Entry
Catalyst
1
2
3
4
5
6
1-(Phenylthio)acetic acid
4-Methoxybenzoic acid
4-Chlorobenzoic acid
Citric acid
2.5
2.5
2.5
15
20
25
20 (min) 91
Sodium citrate
2.5
2
40
65
Benzenesulfonic acid
In the next step, the reaction of indole with H2O2 and
KSCN was tested by using different amounts of citric acid at
room temperature (Table 2). As shown in Table 2, the opti-
mal amount of the catalyst was 10 mol %. In the absence of
catalyst when indole was treated with hydrogen peroxide and
KSCN, no product was obtained. When the amount of cata-
lyst was less than 10 mol %, the yield of product was greatly
reduced. Otherwise, increasing the catalyst loading from 10
to 15 mol % does not significantly change the yield. Also,
the solvent effect was investigated using indole as a substrate.
We carried out the reaction with the same concentration of
the reactants in H2O, MeOH, CH3CN, CH2Cl2, THF, and
AcOEt. Both the yields and the reaction times listed in Ta-
ble 2 suggested that water was the most favorable solvent for
the thiocyanation.
Consequently, 10 mol % citric acid was used in subsequent
experiments. We then applied this reaction to a wide range of
aromatic and heteroaromatic compounds; the results are sum-
marized in Table 3.
A good range of aromatic and heteroaromatic compounds
underwent thiocyanation with high regioselectivities and
excellent yields being observed in all cases (Table 3). The re-
action was mild and equally good for indoles, anilines, and
N- substituted anilines.
As shown in Table 3, indole and electron-rich indoles gave
the desired products in excellent yields (Table 3, entries 1–3).
Also, electron-deficient indoles such as 5-bromoindole af-
forded the corresponding 5-bromo-3-thiocyanato indoles in
good yields, but required longer reaction times (Table 3, en-
try 4). This observation can be attributed to the lower elec-
tron density of such substrates. The thiocyanation reaction
was highly regioselective at the 3-position of the indole ring.
Pyrrole was easily transformed into the monothiocyanated
product within 15 min. After reviewing the reactions for the
heterocycles, we examined the capability of aromatic amines
in the thiocyanation reaction. Electron-rich amines such as o-
toluidine and m-toluidine underwent reaction under the same
conditions, leading to a high production efficiency (Table 3,
entries 9 and 10). Our review showed that electron-deficient
Table 2. Optimization of reaction conditions.
Catalyst
Entry (mol %)
Yield
Solvent
H2O
H2O
H2O
H2O
MeOH
CH3CN
CH2Cl2
AcOEt
THF
Time (h)
5
3
20 (min)
20 (min)
20 (min)
20 (min)
2.5
(%)
15
35
91
90
91
90
40
55
50
1
2
3
4
5
6
7
8
9
1
5
10
15
10
10
10
10
10
2.5
2.5
amines also carry out this reaction, but they need more time
(Table 3, entries 11–14). In N-substituted amines some inter-
esting results were achieved. In all cases, the substrate re-
acted and produced corresponding aryl thiocyanates
(Table 3, entries 6–8 and 16–18). As shown in Table 3, the
substitution was highly regioselective, occurring at the para
position of the aromatics rings.
In comparison with the previously reported method using
other reagents, which requires refluxing conditions for some
substrates, the assistance of ultrasonic irradiation, and a toxic
solvent or oxidant, this method is suitable and has mild and
green reaction conditions.
In conclusion, we have developed an efficient, simple, and
green-mediated thiocyanation of aromatic compounds with
high regioselectivity. The described method has advantages
such as a simple work-up, a short reaction time, is metal
free, uses mild reaction conditions, and a clean production
of the desired products in high yields.
Experimental
All chemicals were purchased from Merck or Fluka Chem-
ical Companies. All known compounds were identified by
comparison of their melting points and spectral data with
Published by NRC Research Press

Khazaei et al.
429
Table 3. Substrate range in the thiocyanation reaction using
Table 3 (continued).
KSCN / citric acid / H2O2 under mild conditions.
Time
(min)
Yield
(%)a
Entry
10
Product
NH2
Time
(min)
20
Yield
(%)a
91
Entry
1
Product
35
88
SCN
Me
N
H
SCN
(1a)
(1j)
NH2
SCN
2
20
82
11
12
45
60
78
N
Br
Me
SCN
(1b)
SCN
3
4
7
88
85
(1k)
NH2
5
Me
CN
N
H
(1c)
SCN
25
SCN
Br
(1l)
NH2
13
14
50
35
72
77
N
H
(1d)
5
6
15
60
93
75
CF3
SCN
N
SCN
H
(1m)
NH2
(1e)
N
CF3
SCN
SCN
(1f)
(1n)
7
8
9
60
60
15
79
81
85
N
15
16
NCS
45
45
89
83
N
H
SCN
(1o)
(1g)
HO
OH
NH
N
SCN
(1h)
NH2
SCN
Me
(1p)
SCN
(1i)
Published by NRC Research Press

430
Can. J. Chem. Vol. 90, 2012
(m/z) = 174 (M+). Anal. calcd for C9H6N2S: C 62.05, H
Table 3 (concluded).
3.47, N 16.08; found: C 62.25, H 3.34, N 16.15.
Time
(min)
Yield
(%)a
Entry
17
Product
1-Methyl-3-thiocyanatoindole (1b)
O
60
65
mp 79–81 °C (lit.54 80–81 °C). FT-IR (KBr): 2146 (SCN).
1H NMR (CDCl3) d: 7.84–7.36 (m, 5H), 3.74 (s, 3H). 13C
NMR (CDCl3) d: 137.1, 135.2, 128.4, 123.4, 121.6, 118.8,
112.1, 110.3, 33.4. MS (m/z) = 188 (M+). Anal. calcd for
C10H8N2S: C 63.80, H 4.28, N 14.88; found: C 64.01, H
4.15, N 14.92.
N
SCN
2-Methyl-3-thiocyanatoindole (1c)
(1q)
mp 97–99 °C (lit.55 99–101 °C). FT-IR (KBr): 2151
18
40
79
1
(SCN), 3395 (NH), 3395. H NMR (CDCl3 d): 8.55 (s, 1H),
O
O
7.71 (d, J = 6.9 Hz, 1H), 7.33–7.23 (m, 3H), 2.49 (s, 3H).
13C NMR (CDCl3) d: 142.1, 135.1, 128.6, 122.9, 121.5,
118.0, 111.3, 88.7, 12.0. MS (m/z) = 188 (M+). Anal. calcd
for C10H8N2S: C 63.80, H 4.28, N 14.88; found: C 63.65, H
4.41 N 14.80.
O
O
N
5-Bromo-3-thiocyanatoindole (1d)
SCN
mp 126–128 °C (lit.53 124–127 °C). FT-IR (KBr): 2146
(SCN), 3351 (NH). 1H NMR (CDCl3) d: 8.87 (br s, 1H,
NH), 7.90–7.15 (m, 5H). 13C NMR (CDCl3) d: 134.6, 132.2,
129.3, 123.1, 121.2, 115.3, 113.7, 111.9, 102.2. MS (m/z) =
251 (M+), 253 (M + 2). Anal. calcd for C9H5BrN2S: C
42.71, H 1.99, N 11.07; found: C 42.55, H 2.12, N 11.07.
(1r)
Note: Reaction conditions: substrate, 1 mmol; H2O2 (30%), 3 mmol;
KSCN, 3 mmol; citric acid, 10 mol %; H2O, 3–5 mL; with stirring.
aIsolated yields.
those reported in the literature. Progress of the reactions was
monitored by TLC using silica gel SIL G/UV 254 plates. The
2-Thiocyanatopyrole (1e)
1H NMR (300 MHz) and 13C NMR (75 MHz) were run on a
Bruker Avance DPX-250 FT-NMR spectrometer (d in ppm).
Microanalysis was performed on a PerkinElmer 240-B micro-
analyzer. Melting points were recorded on a Büchi B-545 ap-
paratus using open capillary tubes.
Liquid bp 175–176 °C (no literature value available). FT-
IR (KBr): 2160 (SCN), 3247 (NH). 1H NMR (CDCl3) d:
9.04 (s, 1H), 7.04–7.00 (m, 1H), 6.68–6.59 (m, 1H), 6.30–
6.29 (m, 1H). 13C NMR (CDCl3 d): 121.2, 120.2, 112.2,
110.9, 109.6. MS (m/z) = 124 (M+).
4- Thiocyanato-N,N-diethylaniline (1f)
General procedure for the preparation of 3-
thiocyanatoindole (1a)
mp 82–84 °C (no literature value available). FT-IR (KBr):
1
2151 (SCN). H NMR (CDCl3) d: 7.5–7.34 (m, 2H), 7.2–
A suspension of indole (0.117 g, 1 mmol), potassium thio-
cyanate (0.294 g, 3 mmol), and citric acid (0.0164 g,
10 mol %) in H2O (3–5 mL) was stirred at room temperature
for 5 min. Then H2O2 (30%, 3 mmol) was added dropwise
(2–5 min). The progress of the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture
was extracted with CHCl3 (2 × 10 mL). Anhydrous Na2SO4
(3 g) was then added to the organic layer and filtered off
after 20 min. CHCl3 was removed and further purification
was achieved by silica gel column chromatography with hex-
ane/AcOEt (5:1).
7.13 (m, 1H), 6.63–6.61 (m, 1H), 3.37(q, J = 7.12 Hz, 4H),
1.146 (t, J = 5.4 Hz, 6H). 13C NMR (CDCl3) d: 149.1,
134.9, 125.2, 121.7, 112.6, 44.5, 12.3. MS (m/z) = 206 (M
+). Anal. calcd for C11H14N2S: C 64.04, H 6.84, N 13.58;
found: C 64.23, H 6.71, N 13.49.
4-Thiocyanato-N,N-dimethylaniline (1g)
mp 71–72 °C (lit.55 70–73 °C). FT-IR (KBr): 2146 (SCN).
1H NMR (CDCl3) d: 7.44 (d, J = 8.7, 2H), 6.69 (d, J = 8.7,
2H), 3.00 (s, 6H). 13C NMR (CDCl3) d: 151.6, 134.5, 113.1,
112.7, 106.3, 40.1. MS (m/z) = 178 (M+). Anal. calcd for
C9H10N2S: C 60.64, H 5.65, N 15.72; found: C 60.45, H
5.84, N 15.65.
Spectral data of the products
Note: Compounds 1f, 1h,1k, 1l, 1m, 1n, 1o, 1p, 1q, and
1r are new. Selected product spectra can found in the Supple-
mentary data.
4-Thiocyanato-N-methylaniline (1h)
mp 45–48 °C (lit.53 46–47). FT-IR (KBr): 2153 (SCN),
1
3-Thiocyanatoindole (1a)
3413 (NH). H NMR (CDCl3) d: 7.15–7.12 (m, 2H), 7.06–
mp 71–73 °C (lit.53 70–71 °C). FT-IR (KBr): 2159 (SCN),
6.82 (m, 2H), 4.70 (s, 1H), 3.32 (s, 3H). 13C NMR (CDCl3)
d: 150.9, 134.6, 132.8, 117.6, 116.4, 114.8, 113.6, 30.3. MS
(m/z) = 164 (M+). Anal. calcd for C8H8N2S: C 58.51, H
4.91, N 17.06; found: C 58.71, H 4.79, N 17.12.
1
3289 (NH). H NMR (CDCl3) d: 8.87 (br s, 1H), 7.83 (d, J =
8.8 Hz, 1H), 7.46–7.23 (m, 4H). 13C NMR (CDCl3) d:
136.06, 131.2, 127.6, 123.8, 121.8, 118.6, 112.2, 91.7. MS
Published by NRC Research Press

Khazaei et al.
431
1
2-Methyl-4-thiocyanatoaniline (1i)
2153, 3300. H NMR (CDCl3) d: 7.43 (d, J = 6.5 Hz, 1H),
6.70 (d, J = 7.1 Hz, 2H), 3.75–3.60 (4H, m), 3.55–3.35 (m,
4H), 2.15 (s, 2H). 13C NMR (CDCl3) d: 151.8, 132.1, 116.5,
114.3, 111.7, 58.7, 55.9. MS (m/z) = 238 (M+). Anal. calcd
for C11H14N2O2S: C 55.44, H 5.92, N 11.76; found: C 55.66,
H 5.79, N 11.85.
mp 62–64 °C (no literature value available). FT-IR (KBr):
1
2153 (SCN), 3369 and 3456 (NH2). H NMR (CDCl3) d:
6.64–7.37 (m, 3H), 3.987 (br s, 2H), 2.12 (s, 3H). 13C NMR
(CDCl3) d: 147.3, 135.1, 132.1, 123.9, 115.8, 112.8, 108.8,
17.2. MS (m/z) = 164 (M+). Anal. calcd for C8H8N2S: C
58.51, H 4.91, N 17.06; found: C 58.29, H 5.03, N 17.15.
4-Thiocyanato-N-phenylmorpholine (1q)
3-Methyl-4-thiocyanatoaniline (1j)
mp 74–76 °C (no literature value available). FT-IR (KBr):
1
mp 70–71 °C. FT-IR (KBr): 2146 (SCN), 3219 and 3337
2156 (SCN). H NMR (CDCl3) d: 7.48 (d, J = 8.29 Hz, 2H),
1
(NH2). H NMR (CDCl3) d: 7.38 (d, J = 7.7 Hz, 1H), 7.65
6.92 (d, J = 8.42 Hz, 2H), 3.88 (t, J = 4.69 Hz, 4H), 3.24–
3.21 (t, J = 4.83 Hz, 4H). 13C NMR (CDCl3) d: 152.5,
133.7, 116.1, 111.9, 111.1, 67.1, 48.06. MS (m/z) = 220 (M+).
Anal. calcd for C11H12N2OS: C 59.97, H 5.49, N 12.72;
found: C 59.79, H 5.65, N 12.85.
(q, J = 6.52 Hz, 2H), 4.1 (br s, 2H), 2.34 (s, 3H). 13C NMR
(CDCl3) d: 149.7, 143.01, 136.3, 117.3, 112.4, 108.4, 21.2.
MS (m/z) = 164 (M+). Anal. calcd for C8H8N2S: C 58.51, H
4.91, N 17.06; found: C 58.71, H 4.75, N 16.96.
3-Bromo-4-thiocyanatoaniline (1k)
4-Thiocyanato-N-phenyl-15-crown-5 (1r)
mp 49–50 °C. FT-IR (KBr): 2156 (SCN), 3233 and 3376
mp 77–80 °C (no literature value available). FT-IR (KBr):
1
(NH2). H NMR (CDCl3) d: 7.23–7.50 (m, 3H), 6.65 (s, 1H),
1
2147 (SCN), 1094 (C–O), H NMR (CDCl3) d: 7.35 (d, J =
4.12 (s, 2H). 13C NMR (CDCl3) d: 144.8, 134.5, 132.6,
117.5, 116.1, 112.7, 109.2. MS (m/z) = 228 (M+), 230
(M + 2). Anal. calcd for C7H5BrN2S: C 36.70, H 2.20, N
12.23; found: C 36.92, H 2.31, N 12.14.
5.5 Hz, 2H), 6.64 (d, J = 6 Hz, 2H), 3.57–3.72 (m, 20H).
13C NMR (CDCl3) d: 149.3, 134.7, 112.8, 105.9, 112.6,
71.2, 70.2, 69.9, 68.01, 52.6. MS (m/z) = 352 (M+). Anal.
calcd for C17H24N2O4S: C 57.93, H 6.86, N 7.95; found: C
58.19, H 6.99, N 7.89.
2-Cyano-4-thiocyanatoaniline (1l)
mp 107–108 °C (no literature value available). FT-IR
1
Supplementary data
(KBr): 2156 (SCN), 2222 (CN), 3360 and 3444 (NH2). H
NMR (CDCl3) d: 7.58–7.28 (m, 2H), 6.83 (s, 1H), 4.96
(br s, 2H). 13C NMR (CDCl3) d: 151.7, 138.4, 137.2, 117.8,
116.3, 111.3, 109.3, 96.7. MS (m/z) = 175 (M+). Anal. calcd
for C8H5N3S: C 54.84, H 2.88, N 23.98; found: C 55.05, H
2.75, N 23.88.
Supplementary data are available with the article through
the journal Web site http://nrcresearchpress.com/doi/suppl/
10.1139/v2012-013.
Acknowledgement
The authors acknowledge financial support for this work
from the Research Affairs Office of Bu-Ali Sina University
(Grant No. 32-1716 entitled: Development of chemical meth-
ods, reagent, and molecules), from the Iranian National
Elites, and also from the Center of Excellence in Develop-
ment of Chemical Method (CEDCM), Hamadan, I.R. Iran.
3-Trifluoromethyl-4-thiocyanatoaniline (1m)
mp 148–150 °C (no literature value available). FT-IR
(KBr): 2160 (SCN), 3275 and 3369 (NH2). 1H NMR
(CDCl3) d: 7.80–7.33 (m, 3H), 4.01 (br s, 2H). 13C NMR
(CDCl3) d: 144.6, 135.3, 125.5, 118.8, 117.4, 115.1, 111.7.
MS (m/z) = 218 (M+). Anal. calcd for C8H5F3N2S: C 44.04,
H 2.31, N 12.84; found: C 44.26, H 2.43, N 12.75.
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2-Trifluoromethyl-4-thiocyanatoaniline (1n)
mp 119–120 °C (no literature value available). FT-IR
(KBr): 2158 (SCN), 3395 and 3435 (NH2). 1H NMR
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5-Thiocyanatoindoline (1o)
mp 59–60 °C (no literature value available). FT-IR (KBr):
1
2216 (SCN), 3420 (NH). H NMR (CDCl3) d: 7.19–6.92 (m,
3H), 5.20 (br s, 1H), 4.02 (t, J = 9.7 Hz, 2H), 3.23 (t, J =
8.5 Hz, 2H). 13C NMR (CDCl3) d: 142.1, 128.1, 127.8,
127.4, 122.3, 114.89, 110.3, 50.7, 28.51. MS (m/z) = 176
(M+). Anal. calcd for C9H8N2S: C 61.34, H 4.58, N 15.90;
found: C 61.56, H 4.45, N 15.95.
4-Thiocyanato-N-phenyl-2,2-iminodiethanol (1p)
mp 66–69 °C (no literature value available). FT-IR (KBr):
Published by NRC Research Press

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