A new application for diethyl azodicarboxylate: Efficient and regioselective thiocyanation of aromatics amines

Article abstract of DOI:10.1016/j.tetlet.2010.04.096

Highly regioselective thiocyanations of indoles, anilines and pyrrole are achieved via an efficient and simple protocol using NH₄SCN and diethyl azodicarboxylate (DEAD) as a mild oxidant.

Full text of DOI:10.1016/j.tetlet.2010.04.096

Tetrahedron Letters 51 (2010) 3508–3510
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Tetrahedron Letters
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A new application for diethyl azodicarboxylate: efficient and regioselective
thiocyanation of aromatics amines
*
*
Nasser Iranpoor , Habib Firouzabadi , Dariush Khalili, Rezvan Shahin
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly regioselective thiocyanations of indoles, anilines and pyrrole are achieved via an efficient and sim-
Received 31 January 2010
Revised 11 April 2010
Accepted 23 April 2010
Available online 28 April 2010
ple protocol using NH
4
SCN and diethyl azodicarboxylate (DEAD) as a mild oxidant.
Ó 2010 Elsevier Ltd. All rights reserved.
Significant attention is being devoted to organosulfur com-
pounds. Among these compounds, thiocyanates play an important
role in organic synthesis1 and in pharmaceuticals.2 Thiocyano
substituted compounds are useful intermediates in the synthesis
of sulfur-containing heterocycles, in which the thiocyanate group
can be readily transferred to other sulfur-bearing functionalities
such as sulfides, cyanothiolated compounds,4 or desulfurated to
nitriles.5 Aromatic thiocyanates have become important interme-
diates for the preparation of heterocycles, especially as precursors
for agrochemicals, dyes, and drugs.6 Due to the versatility of the
thiocyanate group in heterocyclic chemistry, various methods have
been developed for the thiocyanation of arenes; these include the
4
of 1:1.8:2.5 (indole:DEAD:NH SCN) was found to be the most suit-
able, and decreasing the amount of DEAD or ammonium thiocya-
nate increased the reaction time and lowered the yield. The
substrate scope of this reaction was then examined using various
arenes under the optimized conditions, Table 1.
In general, this reaction provided good-to-excellent yields with
3
18
all the substrates tested. As shown in Table 1, electron-rich indoles
gave the desired products in excellent yields (Table 1, entries 2 and
6). Also, electron- deficient indoles such as 5-bromo- and 5-nitroin-
dole reacted with ammonium thiocyanate and DEAD to afford the
corresponding 3-thiocyanatoindole derivatives 1c and 1d in good
yields, but required longer reaction times (Table 1, entries 3 and
4). This observation can be attributed to the lower electron density
7
8
2
9
use of FeCl
cyanatosuccinimide, DDQ
tion via DDQ,
thiocyanation via SCN , and Mn(OAc)
3 2
, Oxone, I /MeOH, ceric ammonium nitrate, N-thio-
1
0
11a
and ultrasound-assisted thiocyana-
of such substrates. The addition was highly regioselective occurring
1
1b
12
8,14
montmorillonite K10 clay,
electrochemical
at the 3-position of the indole ring.
Next, various anilines were
ꢀ
13
14
3
.
However, difficulties
converted into the respective 4-thiocyanatoanilines 1g–l in high to
excellent overall yields (Table 1, entries 7–12). The reactions were
clean and the products were obtained with high para-selectivity.
However, in the case of a para-substituted aniline (Table 1, entry
14), ortho thiocyanation occurred in high yield. We also used
3-methoxyaniline as a substrate for the electrophilic thiocyanation
reaction, however, no reaction was observed (Table 1, entry 13). Pyr-
role was easily transformed into the mono-thiocyanated product
associated with the use of these reagents include the use of
strongly acidic or oxidizing conditions, low overall yields, high
temperatures and long reaction times. Diethyl azodicarboxylate
(
DEAD) is a valuable reagent in organic synthesis especially with
15
reference to the Mitsunobu reaction. Recently, Grée and Cao dis-
closed an expedient approach to ketones by oxidation of alcohols
with DEAD. Thus, in continuation of our work on thiocyanation,
1
6
17
0
we were interested in the application of DEAD as a mild oxidant for
aromatic thiocyanation. In the present work, we describe an effi-
cient protocol for the selective thiocyanation of indoles, pyrrole
and anilines using NH SCN and DEAD.
4
To identify new conditions for the synthesis of aryl thiocya-
nates, we began with an investigation of the conversion of indole
(1n) within 2.5 h. For construction of a dithiocyanated pyrrole 1n
a longer reaction time was required (15 h). Under optimized condi-
tions, when phenol or anisole was used as the substrate, no reaction
occurred and the starting materials were recovered after periods of
up to two days. In comparison with the reported method using DDQ
1
1a
which requires refluxing conditions
for some substrates, or the
into its corresponding indole thiocyanate using DEAD and NH
4
SCN
as a model reaction (Scheme 1).
SCN
A solvent screen revealed that acetonitrile was the best for this
reaction. The stoichiometry of the reactants was also varied. A ratio
DEAD, NH SCN
4
CH CN, r.t.
3
N
H
N
H
*
Corresponding authors. Tel.: +98 711 2284822; fax: +98 711 2280926.
1a
E-mail addresses: iranpoor@susc.ac.ir (N. Iranpoor), firouzabadi@susc.ac.ir (H.
Firouzabadi).
4
Scheme 1. Synthesis of 3-thiocyanatoindole using DEAD and NH SCN.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.096

N. Iranpoor et al. / Tetrahedron Letters 51 (2010) 3508–3510
3509
Table 1
Substrate scope in the thiocyanation reaction of arenes using NH
SCN and DEADa
Productb
4
Entry
Substrate
Yieldc (%)
859
Time (min)
SCN
N
H
1
45
30
60
90
45
1a
N
H
H CO
SCN
3
H CO
3
2
3
4
5
912
N
H
1b
N
H
Br
SCN
Br
8111a
8012
7911a
N
1c
H
N
H
O N
SCN
2
O N
2
N
1
d
H
N
H
SCN
CH3
N
H
CH3 1e
N
H
SCN
N
CH3
1f
8811a
6
45
N
CH3
1
g
8011a
7511a
7
8
9
H N
H N
SCN
6
2
2
H N
H
2
N
SCN 1h
2
150
Cl
Cl
8511a
842
120
120
150
90
MeHN
EtHN
PhHN
MeHN
EtHN
PhHN
SCN 1i
SCN 1j
1
1
1
0
1
2
SCN 1k
SCN 1l
792
8111a
(Me) N
(Me) N
2
2
H N
2
1
3
4
—
—
—
OMe
H N
OMe
H N
OMe 1m
2
2
8419
1
60
NCS
1
n
SCN
SCN
N
H
N
H
1
5d
8011a
150
'
n
1
NCS
N
H
1
6
7
HO
—
—
—
—
—
—
1
MeO
a
b
c
4
Molar ratio of arene:DEAD:NH SCN was 1:1.8:2.5.
The products were identified from their spectral data and by comparison with known samples.
Isolated yields.
d
After 15 h, a 15% yield of the bis-adduct was obtained.
assistance of ultrasonic irradiation,11b this method is works under
milder reaction conditions. A proposed reaction mechanism is
shown in Figure 1.
amine was studied. Upon mixing these two reagents, the reaction
changed color from pale-yellow to dark-orange and product I ap-
1
13
peared as a precipitate. H and C NMR spectroscopy of this pre-
cipitate in DMSO-d showed the presence of the NH proton and
Formation of ammonia and DEAD–H
2
II (isolated yield: 71%) ac-
6
counts for the proposed mechanism. In order to prove the interme-
diacy of I as evidence for this mechanism, the reaction between
DEAD and NH SCN in dry acetonitrile and in the absence of any
4
the N–SCN carbon of I at 8.86 and 130.6 ppm, respectively.
To conclude, we have developed an efficient and simple DEAD-
mediated thiocyanation of various indoles, anilines and pyrrole

3
510
N. Iranpoor et al. / Tetrahedron Letters 51 (2010) 3508–3510
H
EtOOC
EtOOC
N
N
N
COOEt
NH SCN
EtOOC
N
N
COOEt
+
NH3
+
4
SCN
I
SCN
H
N
H
N
H
N
COOEt
+
EtOOC
COOEt
N
H
SCN
II
N
H
Figure 1. Proposed reaction mechanism.
with high regioselectivity. This method has advantages including
mild reaction conditions and clean formation of the desired prod-
ucts in high yields.
11. (a) Memaian, H. R.; Mohammadpoor-Baltork, I.; Nikoofar, K. Can. J. Chem. 2007,
5, 930; (b) Memaian, H. R.; Mohammadpoor-Baltork, I.; Nikoofar, K. Ultrason.
8
Sonochem. 2008, 15, 456.
1
1
1
1
2. Chakrabarty, M.; Sarkar, S. Tetrahedron Lett. 2003, 44, 8131.
3. Gitkis, A.; Becker, J. Y. J. Electroanal. Chem. 2006, 593, 29.
4. Pan, X. Q.; Lei, M. Y.; Zou, J. P.; Zhang, W. Tetrahedron Lett. 2009, 50, 347.
5. (a) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K.
V. P. Chem. Rev. 2009, 109, 2551; (b) Sze But, T. Y.; Toy, P. H. Chem. Asian J. 2007,
2, 1340; (c) Dandapani, S.; Curran, D. P. Chem. Eur. J. 2004, 10, 3130; (d)
Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
Acknowledgment
Financial support provided by the Shiraz University research
council is gratefully acknowledged.
1
1
6. Cao, H. T.; Gree, R. Tetrahedron Lett. 2009, 50, 1493.
7. (a) Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N. Tetrahedron 2006, 62, 5498; (b)
Iranpoor, N.; Firouzabadi, H.; Sobhani, S. Synthesis 2004, 290; (c) Iranpoor, N.;
Firouzabadi, H.; Akhlaghinia, B.; Azadi, R. Synthesis 2004, 92; (d) Iranpoor, N.;
Firouzabadi, H.; Azadi, R.; Akhlaghinia, B. J. Sulfur Chem. 2005, 26, 133; (e)
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8. Typical procedure for the preparation of 1a: indole (1 mmol, 0.117 g) was added
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