AlCl3-Promoted Thiocyanation of N-Containing Aromatic and Heteroaromatic Compounds Under Solvent-Free Conditions

Article abstract of DOI:10.1080/10426507.2014.978321

Aluminum chloride/Ammonium thiocyanate (AlCl₃/NH₄SCN) was found to be an effective system for the thiocyanation of some arylamines and indoles to afford the corresponding thiocyanated adducts at room temperature under solvent-free conditions. The efficacy of this combined reagent was also examined in the thiocyanation of pyrrole and isatin. A plausible mechanism of thiocyanation has also been suggested.

Full text of DOI:10.1080/10426507.2014.978321

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Phosphorus, Sulfur, and Silicon and the Related
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Alcl3-Promoted Thiocyanation Of N-Containing
Aromatic And Heteroaromatic Compounds Under
Solvent-Free Conditions
Kobra Nikoofara & Samareh Gorjia
a Department of Chemistry, Faculty of Science, Alzahra University, Vanak, P.O. Box
1993893973, Tehran, Iran.
Accepted author version posted online: 14 Jan 2015.
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To cite this article: Kobra Nikoofar & Samareh Gorji (2015): Alcl3-Promoted Thiocyanation Of N-Containing Aromatic And
Heteroaromatic Compounds Under Solvent-Free Conditions, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2014.978321
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AlCl3-PROMOTED THIOCYANATION OF N-CONTAINING AROMATIC AND
HETEROAROMATIC COMPOUNDS UNDER SOLVENT-FREE CONDITIONS
Kobra Nikoofar,*and Samareh Gorji
Department of Chemistry, Faculty of Science, Alzahra University, Vanak, P.O. Box
1993893973, Tehran, Iran. E-mail: knikoofar@yahoo.com
Abstract Aluminum chloride/Ammonium thiocyanate (AlCl3/NH4SCN) was found to be an
effective system for the thiocyanation of some arylamines and indoles to afford the
corresponding thiocyanated adducts at room temperature under solvent-free conditions. The
efficacy of this combined reagent was also examined in the thiocyanation of pyrrole and isatin. A
plausible mechanism of thiocyanation has also been suggested.
SCN
AlCl3/ NH4SCN
Solvent-free, r.t.
N
N
3 h, 90%
H
H
2a
1a
Running title AlCl3 THIOYANATION OF AROMATIC COMPOUNDS
Keywords Thiocyanation; Indole; AlCl3; Solvent-free conditions
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INTRODUCTION
The thiocyanation of aromatic and heteroaromatic compounds is an important transformation
in both organic synthesis and pharmaceuticals.1,2 Organic compounds containing the thiocyano
group have been used as precursors for agrochemical, dyes, and drugs.3 This moiety is a
significant functionality in several anticancer agents.4 Most applications of thiocyanate motif
have been observed when it is used as a functional group on N-bearing (hetero)arene compounds.
The thiocyanated N-containing chemicals have excessive key application. Nitrogen occurs in all
living organisms, primarily in amino acids and thus proteins and in the nucleic acids (DNA and
RNA).5 Several methods for the thiocyanation of (hetero)aromatic systems using various
reagents such as oxone/NH4SCN,6 N-thiocyanosuccinimde,7 FeCl3/NH4SCN,8 cerric ammonium
nitrate (CAN)/NH4SCN,9 Montmorillonite K-10 clay/NH4SCN,10 Poly(4-diacetoxyiodo)styrene
(PDAIS)/NH4SCN,11 acidic Al2O3/NH4SCN,12 HCl/H2O2/KSCN,13 trichloroisocyanuric acid
(TCCA)/NH4SCN/wet SiO2,14 and citric acid/KSCN/H2O215 have been explored. Although the
reported methods are efficient, but some of them have disadvantages including low yields,
strongly acidic conditions, long reaction times, high temperatures and use of expensive and toxic
reagent or solvent. So developing new protocols for thiocyanation of organic compounds is still
in demand.
Anhydrous AlCl3 is probably the most commonly-used Lewis acid. This white relative non-toxic
powder with LD50 = 3730 mg/kg is moisture-adsorbent. It has been extensively used as a strong
Lewis acid in many organic reactions such as Friedel-Crafts reactions and Fries
rearrangement.16,17 Recently, AlCl3 has been employed for some other transformations such as
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the synthesis of 5-benzoylacenaphthene,18 selective synthesis of 2-aryl-2H- and 4-aryl-4H-3,5-
diformylpyrans,19 asymmetric aldehydes arylation,20 1,4-dihydropyridines synthesis,21
cycloadditions of activated cyclopropanes and aromatic aldehydes,22 1,2,3,4-
tetrahydroquinolines synthesis,23 and substituted guanidines synthesis.24
In continuation of research interest on thiocyanation of N-containing (hetero)aromatic
organics,25 herein we report AlCl3 as a commercially available and low-cost promoter for
thiocyanation of some N-containing heteroaromatics and N-activated arenes in the presence of
NH4SCN at room temperature under solvent-free conditions (Scheme 1 and Table 2).
RESULTS AND DISCUSSION
To investigate the optimized reaction condition, initial studies were performed by indole 1a
as a substrate model. The results are summarized in Table 1. Optimization of the temperature
effect confirmed that room temperature condition is appropriate (entries 1, 2). By checking
various amounts of NH4SCN and AlCl3, we attended that molar ratio NH4SCN/AlCl3 (2/1)
afforded the best results (entries 2-5).The effect of solvent have also been examined .The data
showed that the solvent-free condition is the most effective situation (entries 2, 6 and 7). In order
to be sure about the promoting role of AlCl3 in thiocyanation reaction, the model reaction was
verified in the presence of 2 mmol of NH4SCN without any AlCl3 (entry 8). Comparison of the
results affirmed the particular promoting activity of AlCl3.
Therefore, performing the reaction with substrates (1 mmol), AlCl3 (1 mmol) and NH4SCN
(2 mmol) at room temperature under solvent-free condition has been chosen as the optimized
situation for our procedure. The result of different aromatic and heteroaromatic thiocyanation has
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been summarized in Table 2. According to data on Table 2, indole 1a, and its electron donating
derivatives such as 2-methyl-indole 1b and 1-methyl indole 1c thiocyanated at their 3-position
successfully. 5-bromoindole 1d as an electron-withdrawing candidate of Indole derivatives
yielded its corresponding 3-thioyanato-5-bromoindole 2d. Isatin 1e as another N-bearing
heteroaromaitc thiocyanated at 5-position successfully. It must be mentioned that literature
reports for isaitn thiocyanation is rare. Carbazole 1f produced its correspondence 4-thiocyanato
derivative prosperously. Pyrrole, as an example of heteroarene, created 2-thiocyanatopyrrole 2g.
This result also demonstrates the regioselectivity of the method as 2,5-dithiocyanatopyrrole
hasn't been obtained. To display the efficacy of AlCl3 for thiocyanation of a wide range of N-
containing organic compounds, we accomplished the thiocyanation reaction with aniline as an N-
activated aromatic example. 4-Thiocyantoaniline 2h was the only product. In the next step, N-
methylaniline, N,N-dimethylaniline and N,N-diethylaniline thiocyanated at their para position
consequently (Table 2, 1i-1k). Creation of 4-thiocyanato-2-iodoaniline 2l demonstrates that
thiocyanation of anilines occurred at para position selectively. Surprisingly, utilizing of 3-
methylindole 1m as another substrate, compound 2m has been gained as the only product.
Characterization of this compound, which followed by comparison of its spectral data with
literature, 10,26 confirmed that it is an autoxidation product of skatole.
Although the tenuous mechanism of thiocyanation is not clear yet, but we have suggested a
plausible mechanism for AlCl3-promoted thiocyanation (Scheme 2). It seems that anhydrous
AlCl3 can create a complex with NH4SCN to form A. Nucleophilic attack of indole 1a to A
which followed by a proton-release leads to the corresponding thiocyanated product 2a. On the
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other hand, AlCl3 as a strong Lewis acid, can produce acid-base complexes with the nitrogen
loan pair in N-containing heteroaromatics like indole and also arylamines like aniline (Scheme 2,
B & C). It is obvious that the intermediate between aniline and AlCl3 B, is more intensive than
C. This Vigorous interaction captivate the nitrogen loan pair of aniline so tightly that the
thiocyanating reaction of aniline 1h hasn't progressed under solvent-free conditions. 4-
Thiocyanatoaniline formation accelerated in the presence of CH3OH as solvent. The solvent
media may weaken the tight complex C and therefore nucleophilic attack of SCN+ to the free
form of aniline causes the product 2h.
Finally, in order to show the superiority of AlCl3/NH4SCN over other thiocyanating systems,
the results of the present study for the synthesis of 3-thiocyanato-2-methylindole 2b are
compared with some other results reported in the literature in Table 3. The data have indicated
that the recent procedure is a noteworthy route for thiocyanation.
CONCLUSION
In summary, AlCl3/NH4SCN has been employed as a novel and highly efficient system for
the thiocyanation reaction of N-bearing (hetero)aromatic compounds at room temperature under
solvent-free conditions. AlCl3 is commercially available, inexpensive and non-volatile chemical
which is commonly found in organic laboratories and could be dehydrated by conventional
heating. This non-corrosive, Lewis acid promotes NH4SCN activation for the nucleophilic attack
of substrates. Furthermore, the regioselectivity of the protocol has been also investigated in
thiocyanation of pyrrole and anilines where the mono-thiocyanatopyrrole and para-
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thiocyanatoanilines corresponding adduct has been gained. In addition, the absence of hazardous
and non-green solvents and easy work-up in addition with wide-range thiocyanating power for
different substrates are some other noteworthy advantages of the reported procedure.
EXPERIMENTAL
General
Chemicals and solvents were purchased from Merck, Aldrich and Alfa Aesar and used
without further purifications except some liquid anilines which have been distilled before usage.
Commercial AlCl3 was heated and its sublimated anhydrous form was used. Melting points were
determined using a Stuart Scientific apparatus and were uncorrected. All products were
-1
identified by their spectral data. IR spectra (KBr discs, 500-4000 cm ) were recorded using a
1
Bruker FTIR model Tensor 27 spectrometer. H-NMR spectra were recorded in CDCl3 solvent
on a Brucker 400 MHz spectrometer. Mass spectra were obtained on Platform II spectrometer
from Micromass; EI mode at 70 eV. The elemental analysis were determined using a
Thermofinnigan Flash EA 1112 series instrument. Preparative layer chromatography (PLC) was
carried out on 20×20 cm2 plates, coated with a 1 mm layer of Merck silica gel PF254, and
prepared by applying the silica as slurry and drying in air. Yields refer to isolated products.
General procedure for thiocyanation of N-containing hetero(aromatic) compounds by
AlCl3/NH4SCN at room temperature under solvent-free condition
A mixture of substrates 1a-m (1 mmol), anhydrous AlCl3 (1 mmol) and NH4SCN (2 mmol)
was stirred at room temperature. The progress of the reaction was monitored by TLC (eluent: n-
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hexane:EtOAc, 9:2). After completion (0.45-7 h), the residue was diluted with distillated water
(20 mL) and extracted with chloroform (2 × 20 mL). The combined organic layer was dried over
MgSO4 and evaporated. The resulting crude product was purified by plate chromatography on
silica gel (PLC) to afford the pure products 2a-m (52-98%, Table 2). All the products were
characterized by comparison of their spectroscopic data (FTIR, 1H-NMR and Mass spectra) with
those of the authentic samples in literature. The spectroscopic data of a selected compound 2l is
given below.
2-Iodo-4-thiocyanatoaniline (2l) Pale brown solid, mp 140 °C; IR (KBr, Cm-1): υ= 3406
1
(NH2), 3269 (NH2), 2068 (SCN), 1599, 1486, 1285, 1108, 766 (N-H), 689 (C-S); H-NMR
(CDCl3, ppm): = 4.39 (br s, 2H, NH2), 6.77 (d, 1H, J= 8.47 Hz), 7.28 (dd, 1H, J= 8.46 & 2.14
Hz), 7.50 (d, 1H, J= 2.14 Hz) ppm; 13C-NMR (CDCl3, ppm): = 146.3. 133.7, 132.1, 119.6,
116.5, 112.1, 109.7; EI-MS (m/z, %) 276 [M+] (86), 217 [M+-HSCN] (45), 202 [M+-SCN, -NH2]
(36), 91 [M+-I, -SCN] (30), 77 [C6H5] (15); Anal. calcd. for C7H5NSI: C, 32.08; H, 1.92; N, 5.34
%, Found: C, 32.10; H, 1.95; N, 5.26 %.
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SCN
AlCl3/ NH4SCN
Solvent-free, r.t.
N
H
N
H
2a
1a
Scheme 1
_
_
AlCl
+
+
NCS
AlCl3
NH4SCN
+
+
3
..
A
N
H
1a
NH4+
AlCl3
SCN
SCN
+
NH
N
H
H+
2a
NH2
..
..
N
H
AlCl3
C (strong acid-base complex)
AlCl3
B (weak acid-base complex)
Scheme 2
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Table 1 Optimization of the reaction conditions for the synthesis of 3-thiocyanatoindole 2a
Temperature
Time
(h)
Yieldb
Entry
Conditiona
(°C)
r.t.
(%)
90
1
2
3
4
5
6
7
8
AlCl3/NH4SCN molar ratio (1/2)/ solvent-free
AlCl3/NH4SCN molar ratio (1/2)/ solvent-free
AlCl3/NH4SCN molar ratio (1.5/2)/ solvent-free
AlCl3/NH4SCN molar ratio (1/1)/ solvent-free
AlCl3/NH4SCN molar ratio (0.5/2)/ solvent-free
AlCl3/NH4SCN molar ratio (1/2)/ MeOHc
AlCl3/NH4SCN molar ratio (1/2)/ CH3CNc
NH4SCN (2 mmol)/ solvent-free
3
3
2
4
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
90
30
45
28
75
80
20
2.5
3
4
6
a1 mmol of indole (1a) was used. bIsolated yields. c5 mL of solvent was used.
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Table 2 Thiocyanation of aromatic and heteroaromatic compounds with NH4SCN in the presence
of AlCl3 under solvent-free conditions at room temperature
Time
(h)
Yield
(%)
mp
Substrate
Product
.(°C)
SCN
Indole
1a
1b
2a
2b
3
1
90
98
101-10212
N
H
SCN
2-Methylindole
1-Methylindole
99-10112
CH3
N
H
SCN
1c
2c
1.45
80
83-8411
N
CH3
SCN
Br
5-Bromoindole
1d
1e
2d
2e
2.5
93
91
127-12911
N
H
O
NCS
Isatin
7
2018
O
N
H
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SCN
Carbazole
1f
1g
1h
1i
2f
2g
2h
2i
6.5
87
52
90-9210
Liquid13
51-528
N
H
6
Pyrrole
SCN
N
H
7
93d
Aniline
NCS
NH2
CH3
N-methylaniline
2
64
Liquid14
NCS
N
H
CH3
CH3
NCS
NCS
N
N,N-dimethylaniline
N,N-diethylaniline
1j
2j
1
80
89
71-7214
C2H5
C2H5
1k
2k
4.45
N
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8215
I
2-Iodoaniline
1l
2l
2.5
71
67
140
NCS
NH2
CH3
H3C
3-Methylindole
1m
2m
0.45
19826
N
H
N
O
H
aAll products were characterized by comparison of their spectroscopic data (IR, 1H-NMR) with
those reported in literature. bYield of isolated product. c Reference of known compounds. d The
reaction performed in the presence of 5 mL CH3OH
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Table 3 Comparison of some other procedures with the present work for the synthesis of
3-thiocyanato-2-methylindole 2ba
Entry
Conditiona
Time
Yield
Ref.
1
2
3
4
5
PDAIS/NH4SCN molar ratio (1.2/2.5)/ CH3CN/ r.t.
FeCl3/NH4SCN molar ratio (1.5/2.5)/ CH2Cl2/ r.t.
K-10 clay/NH4SCN (2 g/3 mmol)/ solvent-free/ 80° C
CAN/NH4SCN molar ratio (2.3/1.2)/ MeOH/ r.t.
AlCl3/NH4SCN molar ratio (1/2)/ solvent-free/ r.t.
1
3
78
92
92
84
98
11
8
3
10
9
0.25
1
This work
a1 mmol of 2-methylindole 1b has been used.
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