IBX: A novel and versatile oxidant for electrophilic thiocyanation of indoles, pyrrole and arylamines

Article abstract of DOI:10.1055/s-0028-1083636

The direct thiocyanation of indoles and pyrrole with ammonium thiocyanate has been achieved using o-iodoxybenzoic acid (IBX) under mild and neutral conditions to produce indol-3-yl and pyrrol-2-yl thiocyanates, respectively, in excellent yields and with h

Full text of DOI:10.1055/s-0028-1083636

PAPER
3779
IBX: A Novel and Versatile Oxidant for Electrophilic Thiocyanation of
Indoles, Pyrrole and Arylamines
I
BX
:
A N
o
h
vel and
V
er
i
satile
O
l
xidant
l
for
E
le
u
ctrophilic Thiocyan
S
ation . Yadav,* Basi V. Subba Reddy, B. Bala Murali Krishna
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax 0091 40 27160512; E-mail: yadav@iict.res.in
Received 17 June 2008; revised 16 August 2008
ance and high yielding reactions without over oxidation
have made the use of IBX common for the oxidation of al-
cohols even in the presence of alkenes, sulfides, and
amino groups9 and in other elegant oxidative transforma-
Abstract: The direct thiocyanation of indoles and pyrrole with am-
monium thiocyanate has been achieved using o-iodoxybenzoic acid
(IBX) under mild and neutral conditions to produce indol-3-yl and
pyrrol-2-yl thiocyanates, respectively, in excellent yields and with
high selectivity. This method is effective even with N-substituted tions.10 Furthermore, there have been no examples of the
arylamines for the preparation of aryl thiocyanates.
use of IBX for the electrophilic thiocyanation of indoles.
Key words: o-iodoxybenzoic acid, electrophilic substitution, in-
doles, aryl thiocyanates, heteroaryl thiocyanates
In this article, we report a direct and metal-free approach
to the thiocyanation of indoles, pyrrole, and arylamines
using IBX in acetonitrile. First, we attempted electrophilic
thiocyanation of 1H-indole (1a) with ammonium thiocy-
anate (2) using a stoichiometric amount of IBX. The reac-
tion went to completion within 15 minutes at room
temperature and the desired product, 3-thiocyanato-1H-
indole (3a), was obtained in 95% yield (Table 1, entry 1;
Scheme 1).
The electrophilic thiocyanation of aromatics and heteroar-
omatics is an important carbon–heteroatom bond-forming
reaction in organic synthesis.1 Aryl and heteroaryl thiocy-
anates are useful intermediates in the synthesis of sulfur-
containing heterocycles.2 They are useful building blocks
for drugs and pharmaceuticals.2b In particular, aryl thiocy-
anates can be easily transformed into various sulfur-
containing functional groups such as thiophenols, by re-
SCN
IBX
NH4SCN
+
duction with lithium aluminum hydride, and aryl nitriles/
MeCN, r.t.
N
H
N
H
disulfides, by aromatic Grignard reagents.3 The thiocyan-
ate functionality is used as a masked mercapto group.
Thus, the direct thiocyanation of aromatic systems is of
prime importance. Generally, aryl/heteroaryl thiocyanates
have been prepared by electrophilic thiocyanation.4 In
contrast, only few reagents such as N-halosuccinimides,
cerium(IV) ammonium nitrate, acidic K10 clay, iodine/
methanol, iron(III) chloride, and Oxone have been uti-
lized for the thiocyanation of indoles.5,6 However, many
of them require a large excess of strong oxidizing agents
and toxic metal thiocyanates and often involve low con-
versions, especially in case of arylamines. Furthermore,
some require high temperatures to obtain satisfactory re-
sults. In view of the versatility of the thiocyanate group in
the fields of drugs and pharmaceuticals, the development
of mild, convenient, and highly yielding protocols is de-
sirable.
15 min
1a
2
3a 95%
Scheme 1
This result provided an incentive to study further reactions
with various indoles. Interestingly, several substituted in-
doles, such as 2-methyl- 1b, 7-ethyl- 1c, 5-methoxy- 1d,
5-nitro- 1e, and 5-bromo-1H-indole (1f) reacted effective-
ly with ammonium thiocyanate (2) to furnish the corre-
sponding 3-thiocyanatoindole derivatives 3b–f (Table 1,
entries 2–6). In addition, N-protected indoles, such as 1-
benzyl- 1g and 1-ethyl-2-phenyl-1H-indole (1h) also par-
ticipated in this reaction (Table 1, entries 7 and 8). Like
indoles, 1H-pyrrole (1i) was also easily transformed into
the monothiocyanato pyrrole 3i using this procedure. In
this case, substitution took place at the 2-position
(Table 1, entry 9); no bis-thiocyanation was observed.
Next, we examined the reactivity of N-substituted ary-
lamines in the thiocyanation. Interestingly, N-alkyla-
nilines such as N-methyl- 1j, N-ethyl- 1k, N-benzyl- 1l,
N,N-dimethyl- 1m, and N,N-diethylaniline (1n) under-
went smooth electrophilic thiocyanation under similar re-
action conditions to produce 4-thiocyanatoanilines
(Table 1, entries 10–14).
Recently, the use of hypervalent iodine reagents as oxi-
dants in organic synthesis has attracted increasing interest
due to their mild, selective, and environmentally benign
oxidizing properties.7 o-Iodoxybenzoic acid (IBX) is one
of the most versatile oxidizing agents due its high effi-
ciency, easy availability, mild reaction conditions, and its
stability to moisture and air.8 Wide functional group toler-
In all cases, the reactions took place rapidly at room tem-
perature with high regioselectivity. As the solvent, aceto-
nitrile appeared to give the best results. No oxidation of
indole was observed under the reaction conditions. The
SYNTHESIS 2008, No. 23, pp 3779–3782
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.11.2008
DOI: 10.1055/s-0028-1083636; Art ID: Z14008SS
© Georg Thieme Verlag Stuttgart · New York

3780
J. S. Yadav et al.
PAPER
1
Table 1 IBX-Promoted Thiocyanation of Indoles, Pyrrole, and
Arylamines with Ammonium Thiocyanate (continued)
products were characterized by H NMR, IR, and mass
spectrometry and also by comparison with authentic sam-
ples.5,6 Mechanistically, the reaction may proceed via the
electrophilic substitution of indole by thiocyanogen
(+SCN) formed in situ from IBX and ammonium thiocy-
anate (Scheme 2).
Entry Substrate
Producta
Time Yieldb
(min) (%)
H
BnN
H
BnN
12
1l
3l 10 90
Table 1 IBX-Promoted Thiocyanation of Indoles, Pyrrole, and
Arylamines with Ammonium Thiocyanate
SCN
Me2N
Et2N
Me2N
13
3m 10 95
3n 10 93
Entry Substrate
Producta
Time Yieldb
(min) (%)
1m
1n
SCN
Et2N
SCN
14
1
1a
1b
1c
3a 10 95
SCN
N
H
N
H
a The products were characterized by NMR, IR, and MS.
b Yield refers to pure products after purification.
SCN
2
3
3b
5
91
N
H
[+SCN]
IBX
+
+
NH4SCN
N
H
SCN
SCN
MeCN
[+SCN]
3c 10 94
N
H
N
H
N
H
N
H
Et
Scheme 2
Et
SCN
MeO
MeO
4
5
6
7
3d
5
91
The scope and generality of this process is illustrated with
respect to various indoles, pyrrole, and arylamines and the
results are presented in Table 1. The effects of various ox-
idizing agents, such as Dess–Martin periodinane, (diace-
toxyiodo)benzene, iodine/methanol, Oxone/methanol,
and iron(III) chloride, were assessed in the thiocyanation
of indole. Of these reagents, IBX was found to be the most
effective oxidant in terms of conversion and reaction time.
1d
1e
1f
N
N
H
H
SCN
O2N
O2N
3e 20 85
3f 15 90
3g 10 95
N
H
N
H
SCN
Br
Br
In conclusion, IBX has proved to be an effective reagent
for the electrophilic thiocyanation of indoles, pyrrole, and
arylamines under extremely mild and neutral conditions.
In addition to its simplicity and efficiency, this method af-
fords the desired thiocyanates in excellent yields in short
reaction times. This method can be used for the thiocya-
nation of even deactivated indoles in an efficient manner.
This method provides a direct access to a wide range of
heteroaryl thiocyanates.
N
H
N
H
SCN
1g
N
Bn
N
Bn
SCN
Ph
8
3h 15 90
1h
Ph
N
Et
N
Et
Melting points were recorded on a Buchi R-535 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-c spectrophotometer using KBr optics. 1H and 13C NMR spec-
tra were recorded on Gemini-200 spectrometer (200 MHz) in
CDCl3 using TMS as an internal standard. MS were recorded on a
Finnigan MAT 1020 mass spectrometer operating at 70 eV. Column
chromatography was performed using E. Merck 60–120, mesh sili-
ca gel.
9
3i 10 84
1i
1j
SCN
N
H
N
H
H
MeN
H
MeN
10
3j 10 92
SCN
Thiocyanates 3; General Procedure
H
EtN
H
EtN
To a stirred soln of indole, pyrrole, or arylamine (1 mmol) and
NH4SCN (2, 2 mmol) in MeCN (10 mL), IBX (1.0 mmol) was add-
ed and the resulting mixture was stirred at r.t. for the appropriate
time (Table 1). After completion of the reaction (TLC), the mixture
was quenched with H2O (15 mL) and extracted with CH2Cl2 (2 × 15
mL). The combined organic extracts were dried (anhyd Na2SO4),
11
3k 10 95
1k
SCN
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IBX: A Novel and Versatile Oxidant for Electrophilic Thiocyanation
3781
concentrated in vacuo, and purified by column chromatography (sil-
ica gel, Merck, 60–120 mesh, EtOAc–hexane, 0.5:9.5) to furnish
pure thiocyanate derivatives 3.
1-Benzyl-3-thiocyanato-1H-indole (3g)6c
Solid; mp 83–85 °C.
IR (KBr): 3431, 3119, 2926, 2149, 1509, 1450, 735 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.30 (s, 2 H), 7.09 (d, J = 6.8 Hz,
2 H), 7.21–7.38 (m, 6 H), 7.40 (s, 1 H), 7.80 (d, J = 6.8 Hz, 1 H).
3-Thiocyanato-1H-indole (3a)5c
Solid; mp 126–128 °C.
IR (KBr): 3343, 3043, 2920, 2157, 1413, 1233, 735, 663, 590 cm–1.
LC-MS: m/z = 265 [M + 1], 227, 208, 197.
1H NMR (200 MHz, CDCl3): d = 7.19–7.40 (m, 4 H), 7.73 (d,
J = 8.1 Hz, 1 H), 9.0 (br s, 1 H, NH).
1-Ethyl-2-phenyl-3-thiocyanato-1H-indole (3h)
Solid; mp 108–110 °C.
LC-MS: m/z = 197 [M + Na], 133, 113, 102, 59.3.
IR (KBr): 3446, 3061, 2968, 2147, 1466, 1338, 745, 698, 616 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.33 (t, J = 7.3 Hz, 3 H), 4.18 (q,
J = 7.3 Hz, 2 H), 7.30–7.81 (m, 9 H).
2-Methyl-3-thiocyanato-1H-indole (3b)
Solid; mp 104–106 °C.
13C NMR (75 MHz, CDCl3): d = 146.1, 136.0, 130.5, 129.7, 129.5,
128.8, 123.5, 121.9, 119.1, 110.6, 39.8, 15.4.
IR (KBr): 3323, 2922, 2644, 2153, 1676, 1404, 740, 658, 549 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.50 (s, 3 H), 7.15–7.38 (m, 3 H),
7.66 (d, J = 7.9 Hz, 1 H), 8.45 (br s, 1 H, NH).
LC-MS: m/z = 279 [M + 1], 252, 222, 102, 81.
13C NMR (75 MHz, CDCl3): d = 141.9, 135.0, 128.6, 122.9, 121.5,
117.9, 112.0, 111.1, 29.6, 11.9.
2-Thiocyanato-1H-pyrrole (3i)
Liquid.
LC-MS: m/z = 189 [M + 1], 179, 162, 131, 89, 59.3.
IR (neat): 3276, 3105, 1596, 1506, 1303, 815, 590 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.21 (m, 1 H), 6.59 (m, 1 H), 6.91
(m, 1 H), 9.22 (br s, 1 H, NH).
7-Ethyl-3-thiocyanato-1H-indole (3c)
Solid; mp 134–136 °C.
13C NMR (75 MHz, CDCl3): d = 124.1, 120.1, 111.1, 110.9, 102.6.
IR (KBr): 3305, 3109, 2965, 2930, 2155, 1421, 1123, 742, 593 cm–1.
1H NMR (200 MHz, CDCl3, DMSO): d = 1.35 (t, J = 7.3 Hz, 3 H),
2.92 (q, J = 7.3 Hz, 2 H), 7.05–7.20 (m, 2 H), 7.54 (d, J = 8.1 Hz, 1
H), 7.67 (s, 1 H), 11.70 (br s, 1 H, NH).
LC-MS: m/z = 125 [M + 1], 99, 66.
N-Methyl-4-thiocyanatoaniline (3j)
Liquid.
13C NMR (75 MHz, CDCl3, DMSO): d = 134.2, 130.8, 127.4, 126.5,
120.6, 120.3, 114.5, 110.9, 88.9, 22.7, 13.2.
IR (neat): 3412, 2893, 2819, 2150, 1596, 1513, 1329, 1183, 818,
673, 523 cm–1.
LC-MS: m/z = 225 [M + Na], 198, 155, 97.
1H NMR (200 MHz, CDCl3, DMSO): d = 2.81 (s, 3 H), 4.03 (br s,
1 H, NH), 6.50 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2 H).
5-Methoxy-3-thiocyanato-1H-indole (3d)
Solid; mp 124–126 °C.
13C NMR (75 MHz, CDCl3): d = 150.9, 134.2, 112.9, 112.6, 106.2,
29.6.
IR (KBr): 3304, 3132, 2152, 1624, 1582, 1485, 1452, 1291, 1201,
1017, 803, 706 cm–1.
LC-MS: m/z = 165 [M + 1].
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H), 6.92 (d, J = 9.0 Hz,
1 H), 7.17 (d, J = 2.7 Hz, 1 H), 7.27 (d, J = 9.0 Hz, 1 H), 7.42 (d,
J = 2.7 Hz, 1 H), 8.75 (br s, 1 H, NH).
N-Ethyl-4-thiocyanatoaniline (3k)
Solid; mp 52–54 °C.
IR (KBr): 3389, 2962, 2925, 2151, 1675, 1596, 1264, 736, 547 cm–1.
13C NMR (75 MHz, CDCl3): d = 155.6, 131.5, 130.7, 128.4, 114.4,
113.0, 112.2, 99.6, 91.1, 55.7.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H), 3.16 (q,
J = 7.1 Hz, 2 H), 3.91 (br s, 1 H, NH), 6.52 (d, J = 8.6 Hz, 2 H), 7.36
(d, J = 8.6 Hz, 2 H).
LC-MS: m/z = 205 [M + 1], 181, 160, 141.
5-Nitro-3-thiocyanato-1H-indole (3e)6a
Solid; mp 206–208 °C.
13C NMR (75 MHz, CDCl3): d = 150.1, 134.6, 113.5, 112.6, 107.0,
37.9, 14.4.
IR (KBr): 3854, 3747, 3360, 2855, 2159, 1651, 1327, 1075, 660 cm–1.
MS (EI): m/z = 178 [M+], 164, 150.
1H NMR (200 MHz, CDCl3, DMSO): d = 7.63 (d, J = 8.5 Hz, 1 H),
7.93 (d, J = 1.5 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 8.61 (d, J = 1.0
Hz, 1 H), 12.43 (br s, 1 H, NH).
N-Benzyl-4-thiocyanatoaniline (3l)
Solid; mp 68–70 °C.
IR (KBr): 3446, 2920, 2855, 2841, 2141, 1588, 1371, 1077, 805,
515 cm–1.
LC-MS: m/z = 242 [M + Na], 205, 133, 102, 85, 59.
1H NMR (200 MHz, CDCl3): d = 4.33 (s, 2 H), 4.38 (br s, 1 H, NH),
6.57 (d, J = 8.5 Hz, 2 H), 7.24–7.36 (m, 7 H).
5-Bromo-3-thiocyanato-1H-indole (3f)
Solid; mp 126–128 °C.
13C NMR (75 MHz, CDCl3): d = 149.8, 138.1, 134.4, 128.6, 127.3,
127.1, 113.8, 112.4, 107.6, 47.4.
IR (KBr): 3310, 2924, 2855, 2640, 2362, 2152, 1679, 1576, 1265,
736, 673 cm–1.
1H NMR (200 MHz, CDCl3, DMSO): d = 7.31 (dd, J = 8.8, 1.4 Hz,
1 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 2.9 Hz, 1 H), 7.81 (d,
J = 1.4 Hz, 1 H), 11.86 (br s, 1 H, NH).
LC-MS: m/z = 241 [M + 1], 201, 181, 145, 122.
N,N-Dimethyl-4-thiocyanatoaniline (3m)
Solid; mp 73–75 °C.
13C NMR (75 MHz, CDCl3): d = 92.3, 112.8, 114.1, 116.2, 121.9,
127.6, 130.4, 131.6, 137.2.
IR (KBr): 2972, 2931, 2151, 1591, 1507, 1271, 1196, 810, 670, 517
cm–1.
LC-MS: m/z = 276 [M + Na], 173, 146, 114, 59.
Synthesis 2008, No. 23, 3779–3782 © Thieme Stuttgart · New York

3782
J. S. Yadav et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 3.02 (s, 6 H), 6.65 (d, J = 8.6 Hz,
2 H), 7.41 (d, J = 8.6 Hz, 2 H).
(3) (a) Toste, F. D.; Laronde, F.; Still, W. J. Tetrahedron Lett.
1995, 36, 2949. (b) Grant, M. S.; Snyder, H. R. J. Am. Chem.
Soc. 1960, 82, 2742.
13C NMR (100 MHz, CDCl3): d = 151.4, 134.2, 112.9, 112.4, 106.2,
40.0.
(4) (a) Kita, Y.; Takeda, T.; Mihara, S.; Whelan, B. A.; Thoma,
H. J. Org. Chem. 1995, 60, 7144. (b) Kelly, T. R.; Kim, M.
H.; Curtis, A. D. M. J. Org. Chem. 1993, 58, 5855.
(5) (a) Toste, F. D.; De Stefano, V.; Still, I. W. Jr. Synth.
Commun. 1995, 25, 1277. (b) Nair, V.; George, T. G.; Nair,
L. G.; Panicker, S. B. Tetrahedron Lett. 1999, 40, 1195.
(c) Wu, G.; Liu, Q.; Shen, Y.; Wu, W.; Wu, L. Tetrahedron
Lett. 2005, 46, 5831.
LC-MS: m/z = 178 [M+], 153, 140, 92, 47.
N,N-Diethyl-4-thiocyanatoaniline (3n)
Liquid.
IR (neat): 3405, 3061, 2923, 2853, 2150, 1593, 1590, 1330, 816,
697, 522 cm–1.
(6) (a) Chakrabarty, M.; Sarkar, S. Tetrahedron Lett. 2003, 44,
8131. (b) Yadav, J. S.; Reddy, B. V. S.; Shubashree, S.;
Sadashiv, K. Tetrahedron Lett. 2004, 45, 2951. (c) Yadav,
J. S.; Reddy, B. V. S.; Krishna, A. D.; Reddy, Ch. S.;
Narsaiah, A. V. Synthesis 2005, 540.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 6.7 Hz, 6 H), 3.37 (q,
J = 6.7 Hz, 4 H), 6.61 (d, J = 9.0 Hz, 2 H), 7.37 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 149.2, 134.8, 112.5, 104.8, 44.4,
12.3.
(7) (a) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: San Diego, 1997. (b) Wirth, T.; Hirt, U. H.
Synthesis 1999, 1271.
MS (EI): m/z = 206 [M+], 191, 164, 137.
(8) (a) Hartman, C.; Meyer, V. Chem. Ber. 1893, 26, 1727.
(b) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(c) Kitamura, T.; Fujiwara, Y. Org. Prep. Proced. Int. 1997,
29, 409.
Acknowledgment
B.B.M.K. thanks CSIR, New Delhi for the award of a fellowship.
(9) Wirth, T. Angew. Chem. Int. Ed. 2001, 40, 2812.
(10) (a) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew.
Chem. Int. Ed. 2002, 41, 993. (b) Nicolaou, K. C.; Barn, P.
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Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233.
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Synthesis 2008, No. 23, 3779–3782 © Thieme Stuttgart · New York