Regioselective thiocyanation of aromatic and heteroaromatic compounds using ammonium thiocyanate and oxone

Article abstract of DOI:10.1016/j.tetlet.2005.06.132

An efficient and regioselective approach for the thiocyanation of indoles, pyrrole, aromatic amino compounds, and 2-methoxycarbazole has been developed using ammonium thiocyanate as a thiocyanation reagent and oxone as an oxidant.

Full text of DOI:10.1016/j.tetlet.2005.06.132

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5831–5834
Regioselective thiocyanation of aromatic and
heteroaromatic compounds using ammonium thiocyanate and oxone
Guaili Wu, Qiang Liu, Yinglin Shen, Wentao Wu and Longmin Wu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Guansu 730000, PR China
Received 18 May 2005; revised 25 June 2005; accepted 27 June 2005
Abstract—An efficient and regioselective approach for the thiocyanation of indoles, pyrrole, aromatic amino compounds, and
2
ꢀ
-methoxycarbazole has been developed using ammonium thiocyanate as a thiocyanation reagent and oxone as an oxidant.
2005 Elsevier Ltd. All rights reserved.
Thiocyanation of aromatic and heteroaromatic com-
pounds is one of the most important reactions in organic
synthesis. The thiocyano substituted compounds are a
useful kind of intermediates in the synthesis of sulfur-
containing heterocycles, in which the thiocyanate group
will be readily transformed into other sulfur-bearing
cyanation of aromatic and heteroaromatic compounds
using ammonium thiocyanate as a thiocyanation
reagent and oxone as an oxidant. The substrates studied
were indoles, anilines, pyrrole, and carbazole. Using
indoles as substrates, the reaction gave unique 3-thio-
cyano substituted indoles in high yield (Scheme 1 and
Table 1).
1
functionalities. They are particularly useful for produc-
2
ing drugs and pharmaceuticals. In view of the versatil-
3
ity of thiocyanate group in heterocyclic construction, it
In a typical experiment, a solution of 117 mg 1a
(1 mmol) and 114 mg ammonium thiocyanate
(1.5 mmol) in 10 mL of methanol was treated with
924 mg oxone (1.5 mmol) and allowed to stir at room
temperature until completion of the reaction, monitored
by TCL. Consequently, it was diluted with water and
extracted with 4 · 15 mL of dichloromethane (DCM).
DCM was then evaporated and the residue was purified
by column chromatography on silica gel (200–300 mesh,
ethyl acetate/hexane) to afford the product as colorless
crystallines. It was recrystallized from dichlorometh-
ane/hexane or ethyl acetate/hexane. The product was
will be of significance to probe the thiocyanation of aro-
matic and heteroaromatic compounds. Several methods
have been developed for the thiocyanation of arenes by
4
,5
using various reagents under certain conditions. Yet,
only a limited number of reagents, such as bromine/
5
a
potassium thiocyanate (only for indoles), N-thiocy-
anatosuccinimide (only for 5-methoxy-2-methylindole
5
b
and accompanied by two bisthiocyanates),
ceric
5
c
5d
ammonium nitrate (CAN), acidic montK10clay,
iodine/methanol, etc., have been applied to the thiocy-
2
anation of indoles. However, these methodologies suffer
from one or more drawbacks such as the less availability
1
13
identified by H and C NMR, MS, IR, and element
5
a,b
6
or hard preparation of starting materials,
the require-
analysis. IR spectrum showed the characteristic peak
ment for a large excess of strong oxidizing reagents, the
toxicity of metal thiocyanates, low yields for some
5
c
compounds, and performances under certain special
SCN
5
d
conditions.
Hence, a requirement for developing
alternative synthesis routines accessible to the thiocya-
nation of aromatic and heteroaromatic compounds is
in high demand. In the present work, we will report a
novel, efficient, and regioselective approach for the thio-
Oxone
+
NH SCN
4
CH OH, rt
3
N
H
N
H
1
a-1f
2a-2f
Keywords: Thiocyanation; Oxone; Ammonium thiocyanate.
isolated yields of the products up to 98%
*
Corresponding author. Tel.: +86 931 8912500; fax: +86 931
625657; e-mail: nlaoc@lzu.edu.cn
8
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.132

5832
G. Wu et al. / Tetrahedron Letters 46 (2005) 5831–5834
À1
Table 1. Thiocyanation of aromatic and heteroaromatic compounds
with oxone in methanol at room temperature
of –SCN at 2160 cm
7
and the –C–S stretching at
À1
02 cm . The results are listed in Table 1.
a
b
Substrate
Product
t
Yield
(%)
(
min)
The products (2a–f) from indoles (1a–f) showed that the
mono-thiocyanation uniquely occurred at the 3-position
of indole ring. As for 2-methoxycarbazole (1g), the
mono-thiocyanation still took place at the 3-position
of benzene ring. Pyrrole (1h) was also easily transformed
into the mono-thiocyanated product (2h ) within
23 min. The dithiocyanated product (2h ) will be formed
with a longer reaction time of 12 h. Therefore, under the
properly controlled reaction time and amount of ammo-
nium thiocyanate, only 2h will be yielded.
SCN
4
3
2
98
90
N
H
N
1
a
H
a
2
a
SCN
b
N
1
H
N
a
H
1b
2b
SCN
The solvent effect on product yields was investigated
using 1a as a substrate. Both the yields and reaction
times listed in Table 2 suggest that methanol appears
to be very favorable for thiocyanations.
N
30
96
98
N
1c
2c
SCN
H CO
3
H3CO
Potassium peroxymonosulfate is a cheap and readily
accessible oxidizing reagent. It is commonly referred to
as oxone (2KHSO ÆKHSO ÆK SO ) and is a versatile
oxidant for transformation of a wide range of functional
groups. These reactions generally occur at lower tem-
peratures. Thus, they will provide a larger margin of
safety. In addition, oxone is present as solid. It has an
advantage of precise weighed amount of it being used
in the reaction.
2
1
ꢁ
N
H
5
4
2
4
N
H
1
d
2d
7
SCN
Br
Br
2
1
5
8
91
94
N
H
N
H
1
e
2
e
SCN
O2N
O2N
Aromatic amino compounds (1i and k) were readily
converted to the mono-thiocyanated products (2i and
k) with high para-selectivity. Since aromatic amino com-
pounds could be oxidized, some highly polar by-prod-
ucts, easily dissolvable in water, were formed. It led to
a decreased yield of thiocyanated products.
N
H
N
H
1
f
2
f
SCN
OCH3
OCH3 30
97
83
N
H
N
In order for the reaction mechanism to be proposed, the
reduction potential of oxone and the oxidation potential
of indole and ammonium thiocyanate were determined
1g
H
2g
8
in anhydrous methanol. The reduction and oxidation
2h
a
N
potentials of oxone and indole were estimated to be
NCS
H
+
0.325 V and À1.050 V, respectively. Yet, ammonium
2
ha
+
thiocyanate exhibited no oxidation potential. So, it
might be assumed that oxone oxidized indole rather
than ammonium thiocyanate. The oxidation occurs at
the C–C double bond on the hetero-, five-membered
N
H
1
2
5
5
1h
SCN
2h
b
8
N
H
NCS
NCS
+
Å
ring of indole, giving a cation radical of indole (1-R ),
2
hb
which was stabilized by a resonance effect. It was fol-
À
lowed by nucleophilic attack of SCN at the 3-position.
Å
63
71
The radical (1-R ) so formed then undergoes a 3-H-
abstraction by OH generated from oxone during its
reduction, affording the end product, as depicted in
NH2
NH2
Å
9
2
i
1i
NCS
NCS
CH3
CH3
30
N
H
Table 2. Solvent effects on the thiocyanation of 1a
NH(CH3)
a
b
2
j
Solvent
Time (h)
Yield (%)
1j
Methanol
Acetonitrile
Tetrahydrofuran
Dichloromethane
Carbon tetrachloride
0.7
8
48
48
48
98
98
97
53
0
N
2
3
80
N(CH3)2
CH3
1k
2k
a
a
The reaction time.
Isolated yields of the products after column chromatography.
The reaction time.
Isolated yields of the products after column chromatography.
b
b

G. Wu et al. / Tetrahedron Letters 46 (2005) 5831–5834
5833
H
-SCN
NCS -
+
Oxone
+
.
.
H
N
N
N
H
H
.
H
1
1-R+
-R+
.
1
.OH
H
NCS
NCS
SCN
H
H
-
H2O
.
.
H
N
N
N
H
H
H
1
-R.
2
Scheme 2.
Scheme 2. Otherwise, the effect of solvent on the thio-
cyanation indicates that polar solvents highly favor the
thiocyanation. It implies that: (a) a development of
charge separation or a formation of ionic species most
likely occur, and (b) the nucleophilicity of SCN may
be enhanced.
6. Data for the selected products: compound 2a, solid, mp 72–
7
7
2
3 ꢂC; IR (KBr) mmax 3344, 3389, 2158, 1453, 1416, 1234,
À1
1
36, 667, 592 cm ; H NMR (300 MHz, CDCl ) d 7.30 (m,
3
H, J = 9.9 Hz, J = 6.9 Hz), 7.42 (m, 1H, J = 9.9 Hz,
À
J = 7.2 Hz), 7.48 (d, 1H, J = 3 Hz), 7.08 13(dd, 1H,
J = 5.7 Hz, J = 3 Hz), 8.70 (br s, 1H, NH); C NMR
(
1
7
75 MHz, CDCl ) d 135.9, 131.1, 127.5, 123.7, 121.8, 118.5,
3
+
12.2, 112.1, 91.52; MS (EI) m/z 174 (M ), 148, 142, 120,
7, 45. Anal. Calcd for C S: C, 61.8; H, 3.5; N, 16.20;
This approach, due to the commercial availability of
reagents, mild reaction conditions, and good yields
of mono-thiocyanation products, makes it accessible to
organic preparations.
9 6 2
H N
S, 18.4. Found: C, 62.0; H, 3.5; N, 16.1; S, 18.4. Compound
2d, solid, mp 113–115 ꢂC; IR (KBr) m 3304, 3132, 2152,
max
1624, 1582, 1485, 1452, 1408, 1291, 1201, 1161, 1017, 803,
À1
1
7
6
1
06 cm ; H NMR (300 MHz, CDCl ) d 3.900 (s, 3H),
3
.926 (dd, 1H, J = 2.4 Hz, J = 2.7 Hz, J = 9 Hz), 7.17 (d,
H, J = 2.4 Hz), 7.27 (d, 1H, J = 9 Hz), 7.42 (d, 1H,
J = 2.7 Hz), 8.754 (s, 1H); C NMR (75 MHz, CDCl
Acknowledgment
1
3
3
) d
1
5
55.6, 131.5, 130.7, 128.4, 114.4, 113.0, 112.2, 99.6, 91.1,
5.7; MS (EI) m/z 204 (M ), 189, 178, 161, 134, 102. Anal.
The authors thank The Natural Science Foundation of
China for financial support (No. 20272022).
+
Calcd for C H N OS: C, 58.7; H, 3.5; N, 13.9; O, 7.9; S,
1
0
8
2
1
5.8. Found: C, 58.8; H, 3.9; N, 13.7; O, 7.8; S, 15.6.
Compound 2g, solid, mp 177–179 ꢂC; IR (KBr) mmax 3393,
References and notes
2155, 1603, 1461, 1444, 1313, 1253, 1230, 1196, 1164, 769,
À1
1
7
50 cm ; H NMR (300 MHz, CD COCD ) d 3.385 (s,
3 3
1
. See reviews: (a) Wood, J. L. In Organic Reactions; Wiley:
New York, 1967; Vol. 3, pp 240–266; (b) Kelly, T. R.; Kim,
M. H.; Certis, A. D. M. J. Org. Chem. 1993, 58, 5855.
. Yadav, J. S.; Reddy, B. V. S.; Shubashree, S.; Sadashiv, K.
Tetrahedron Lett. 2004, 45, 2951.
. (a) Wood, J. L. In Organic Reactions; Adams, R., Ed.; John
Wiley and Sons: New York, 1946; Vol. 3, Chapter 6; (b)
Guy, R. G. In The Chemistry of Cyanates and Their Thio
Derivatives; Patai, S., Ed.; John Wiley & Sons: New York,
1H), 4.036 (s, 3H), 7.216 (t, 1H, J = 7.5 Hz), 7.28 (s, 1H),
7.38 (t, 1H, J = 7.5 Hz), 8.11 (d, 1H, J = 8 Hz), 8.11(d, 1H,
1
3
J = 8 Hz), 8.34 (s, 1H); C NMR (75 MHz, CD COCD ) d
3 3
2
3
157.1, 143.0, 140.06, 125.6, 122.5, 119.9, 117.8, 111.7, 111.2,
+
101.8, 94.7, 56.3; MS (EI) m/z 254 (M ), 239, 211, 153, 140,
127, 69, 63. Compound 2h , colorless liquid, IR (KBr) mmax
a
3336, 2160, 1531, 1423, 1120, 1076, 1029, 821, 737,
À1
1
681 cm
3
; H NMR (300 MHz, CDCl ) d 6.273 (dd, H,
J = 3 Hz, J = 6.3 Hz), 6.643 (m, 1H, J = 1.5 Hz, J =
1
977, Part 2, Chapter 18, p 819.
3.6 Hz,J = 3.9 Hz), 6.968 (m, 1H, J = 1.5 Hz, J = 3 Hz,
1
3
4
. (a) Soderback, E. Acta Chem. Scand. 1954, 8, 1851; (b)
Angus, A. B.; Bacon, R. G. R. J. Chem. Soc. 1958, 774; (c)
Uemura, S.; Okano, M.; Ichikawa, K. Bull. Chem. Soc. Jpn.
J = 4.5 Hz), 8.917 (s, 1H, NH); C NMR (75 MHz,
CDCl ) d 124.3, 120.1, 111.1, 110.9, 102.8; MS (EI) m/z
3
+
b
124 (M ), 98, 70, 39. Compound 2h , colorless solid, mp
1
973, 46, 3254; (d) Uemura, S.; Onoe, A.; Okazaki, H.;
99–102 ꢂC; IR (KBr) mmax 3273, 3124, 2161, 1522, 1415,
À1
1
Okano, M. Bull. Chem. Soc. Jpn. 1975, 48, 619; (e) Kita, Y.;
Takada, T.; Mihara, S.; Whelan, B. A.; Tohma, H. J. Org.
Chem. 1995, 60, 7144; (f) Khazei, A.; Alizadeh, A.; Vaghei,
R. G. Molecules 2001, 6, 253.
1386, 1229, 1101, 1032, 799, 689, 539, 403 cm ; H NMR
(300 MHz, CDCl ) d 1.487 (d, 2H, J = 2.4 Hz), 4.76 (s, 1H);
C NMR (75 Hz, CDCl ) d 121.2 (2C), 110.9 (2C), 109.4
3
1
3
3
+
(2C); MS (EI) m/z 181(M ), 123, 96, 69. Anal. Calcd for
5
. (a) Grant, M. S.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82,
6 3 3 2
C H N S
: C, 40.2; H, 1.3; N, 23.56; S, 34.91. Found: C,
2
742; (b) Toste, F. D.; Stefano, V. D.; Still, I. W. J. Synth.
39.7; H, 1.6; N, 23.2; S, 34.91. Compound 2i, solid, mp 51–
52 ꢂC; IR (KBr) mmax 3420, 3347, 3245, 2144, 1636, 1594,
Commun. 1995, 25, 1277; (c) Nair, V.; George, T. G.; Nair,
L. G.; Panicker, S. B. Tetrahedron Lett. 1999, 40, 1195; (d)
Chakrabarty, M.; Sarkar, S. Tetrahedron Lett. 2003, 44,
À1
1
1494, 1298, 1176, 823, 520 cm
CDCl
3
(d, 2H, J = 8.7 Hz); C NMR (75 Hz, CDCl ) d 148.8,
; H NMR (300 MHz,
3
) d 3.95 (br s, 2H, NH), 6.67 (d, 2H, J = 8.7 Hz), 7.32
13
8
131.

5834
G. Wu et al. / Tetrahedron Letters 46 (2005) 5831–5834
+
1
1
4
2
34.5 (2C), 116.0 (2C), 112.4, 109.4; MS (EI) m/z 150 (M ),
on an electrochemical analyzer (model CHI 760B), which
was connected to a PC with the Origin 6.0 software. One Pt
flag was used as the working electrode, another Pt flag
24, 118, 106, 80, 65. Anal. Calcd for C
7
H N
6 2
S: C, 56.4; H,
.1; N, 18.7; S, 20.8. Found: C, 56.0; H, 4.0; N, 18.7; S,
1.3.
as the auxiliary electrode, and HgCl
2
/Hg as the refer-
7
8
. Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117,
and references cited therein.
. Redox potentials were measured in anhydrous methanol at
ambient temperature using cyclic voltammetry performed
ence electrode. NaClO
electrolyte.
9. Kennedy, R. J.; Stock, A. M. J. Org. Chem. 1960, 25,
4
was applied to a background
1901.