Facile method for thiocyanation of activated arenes using iodic acid in combination with ammonium thiocyanate

Article abstract of DOI:10.1080/00397910802663402

A facile method for direct thiocyanation of activated arenes using iodic acid in combination with ammonium thiocyanate is described.

Full text of DOI:10.1080/00397910802663402

This article was downloaded by: [Northeastern University]
On: 03 June 2013, At: 13:21
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Facile Method for
Thiocyanation of Activated
Arenes Using Iodic Acid in
Combination with Ammonium
Thiocyanate
a
a
Ulhas S. Mahajan & Krishnacharya G. Akamanchi
a
Department of Pharmaceutical Sciences and
Technology, Institute of Chemical Technology,
Matunga, Mumbai, India
Published online: 26 Jun 2009.
To cite this article: Ulhas S. Mahajan & Krishnacharya G. Akamanchi (2009): Facile
Method for Thiocyanation of Activated Arenes Using Iodic Acid in Combination with
Ammonium Thiocyanate, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:15, 2674-2682
To link to this article: http://dx.doi.org/10.1080/00397910802663402
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,

sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

1
Synthetic Communications , 39: 2674–2682, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663402
Facile Method for Thiocyanation of Activated
Arenes Using Iodic Acid in Combination
with Ammonium Thiocyanate
Ulhas S. Mahajan and Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute
of Chemical Technology, Matunga, Mumbai, India
Abstract: A facile method for direct thiocyanation of activated arenes using iodic
acid in combination with ammonium thiocyanate is described.
Keywords: Activated arenes, ammonium thiocyanate, iodic acid, thiocyanation
Aromatic thiocyanation of activated arenes is an important synthetic
transformation and is frequently used as an intermediate step in synthesis
[1]
of various heterocyclic compounds. In addition, thiocyanate function-
ality can be easily transformed into other functionality such as thiophe-
[
nols by reduction with aluminium hydride, and it can be used as a
2]
[
3]
cyanide-free source for the cyanation of aryl boronic acid. Utility of
thiocyanates in synthesis of sulfur-containing thiosulfonates, which were
coupled fruitfully to the 5,6-dihydropyran-2-one ring to give products
[
4]
that showed excellent HIV protease activity, has been demonstrated.
A number of protocols are available to achieve thiocynation of aro-
matic and heteroaromatic compounds, such as oxone=ammonium thiocya-
[
5a]
[5b]
nate,
thiocyanate,
ammonium thiocynate,
iodine=ammonium thiocyanate,
ferric chloride=ammonium
ceric ammonium nitrate=
[
5c]
[6a]
N-thiocyanatosuccinimide,
[6b]
1
[6c]
Selectfluor =sodium cyanate, acidic K-10
phenyliodine(III) bis(trifluoroacetate)
[6d]
clay=ammonium thiocyanate,
Received October 5, 2008.
Address correspondence to Krishnacharya G. Akamanchi, Department of
Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Matunga, Mumbai 400 019, India. E-mail: kgap@redifmail.com
2
674

Thiocyanation of Activated Arenes
2675
[
7a]
[7b]
(
and diacetoxyiodobenzene=ammonium thiocyanate.
PIFA)=trimethylsilylisothiocyanate (TMS-NCS),
PhICl =PbSCN,
2
[
7c]
However, these
methods suffer from one or the other drawbacks and hence there is scope
for new methods.
In particular, reaction systems based on hypervalent iodine com-
[
7a]
[7b]
pounds such as PIFA=TMS-NCS,
yiodobenzene=ammonium thiocyanate
also suffer from drawbacks of either being expensive and moisture sensi-
PhICl =PbSCN,
and diacetox-
2
[7c]
used for this transformation
[
7a]
[7b]
tive
and indole.
and is employed as an oxidant for many synthetic transformations, such
requiring hazardous reagents,
or being unsuitable for phenols
[
7c]
Iodic acid (HIO ) is a readily accessible crystalline solid
3
[8a]
[8b]
[8c]
as oxidation of sulfides, iodination, and nitrosation. This reagent
has several advantages: it is nontoxic, easy to handle, and cost-effective.
In continuation of our work on the development of useful synthetic
methodologies using hypervalent iodine compounds, we report a new
combination of iodic acid with ammonium thiocyanate as an effective
reagent system for thiocyanation of activated arenes. Scheme 1.
[
9]
Reaction conditions were optimized using N,N-dimethylaniline as a
model substrate. It was treated with 1 equiv of iodic acid in combination
with a stoichiometric amount of ammonium thiocyanate at room tempera-
ture in acetonitrile as a solvent, and the corresponding 4-thiocyanato-N,N-
dimethylaniline was isolated with excellent regioselectivity in 60% yield.
Investigations were carried out by changing the solvent and increasing
the molar ratios of iodic acid and ammonium thiocyanate in relation to
N,N-dimethylaniline. The best results were obtained with 1.5 equiv of
iodic acid and 2.2 equiv of ammonium thiocyanate in chloroform as
solvent. Other hypervalent iodine compounds, such as Dess–Martin per-
iodinane (DMP), o-iodoxylbenzoic acid (IBX), and HIO in combination
4
with ammonium thiocyanates, were also studied using chloroform as
solvent, and only HIO was found to be viable for this transformation.
4
A series of arenes were subjected to thiocyanation under the
optimized reaction conditions. Only activated arenes reacted to give
thiocyanated products, and deactivated arenes failed to react. Even
Scheme 1. Thiocyanation of activated arenes.

2676
U. S. Mahajan and K. G. Akamanchi
a
Table 1. Thiocyanation of arenes using iodic acid=ammonium thiocyanate
Time
(min) Yield (%)
b
Entry
1
Substrate
Product
25
88
2
3
20
90
25
92
4
5
6
30
20
25
88
94
90
7
8
25
35
92
84
(
Continued )

Thiocyanation of Activated Arenes
2677
Table 1. Continued
Time
(min) Yield (%)
b
Entry
9
Substrate
Product
25
15
25
87
86
92
1
1
0
1
1
2
30
82
1
1
3
4
35
84
—
d
NR
360
c
EWG ¼ -NO , -COOH
2
a 1
All products were characterized by H NMR and IR, and their physical
properties were compared with the reported values.
b
Isolated yield.
EWG ¼ electron-withdrawing group.
c
d
NR ¼ no reaction.
though iodic acid is acidic in nature, aniline, N,N-dialkylatedbenzena-
mines, phenol, and anisole reacted efficiently and afforded the
corresponding thiocyanato derivatives with good to excellent yields
(
Table 1, entries 1–5 and 10–12). Chemoselectivity was observed when
N-benzyl-N-methylbenzenamine and N,N-diallylbenzenamine were
reacted under the reaction conditions to give N-benzyl-N-methyl-4-
thiocyanatobenzenamine and N,N-diallyl-4-thiocyanatobenzenamine,
respectively (Table 1, entries 6 and 7) without affecting allylic and

2678
U. S. Mahajan and K. G. Akamanchi
benzylic positions. Heteroaromatic compounds including indole and
thiophene thiocyanated under the reaction conditions and gave the
corresponding thiocyanato derivatives (Table 1, entries 8 and 9). In
the case of p-bromoaniline where para position was blocked, it reacted
completely to give 2-amino-6-bromobenzothiozole in 84% yield as the
sole product, indicating ortho thiocyanation followed by cyclization
(Table 1, entry 13).
When the reaction was performed with electron-deficient aromatic
substrates, such as nitrobenzene and benzoic acid, reaction did not occur
Table 1, entry 14). In all the cases, only single compounds were isolated,
(
indicating that the method provides regioselective monothiocyanation.
In conclusion, we have developed a simple, efficient, and rapid
method for regioselective thiocyanation of activated arenes including
phenols, indoles, and anilines using a combination of iodic acid and
ammonium thiocyanate. Because it is complementary to existing methods
and the reagents are inexpensive, easily accessible, and less hazardous, the
method may find wide utility.
GENERAL EXPERIMENTAL PROCEDURE
A Substrate (5 mmol) was added immediately in one portion to a stirred
red-colored suspension of iodic acid (1.32 g, 7.5 mmol) and ammonium
thiocyanate (0.836 g, 11 mmol) in 15 mL of chloroform. The reaction mix-
ture was stirred at room temperature until complete consumption of
starting material was observed by thin-layer chromatography (TLC).
After completion of the reaction, the reaction mixture was diluted by
adding chloroform (30 mL) and was washed with saturated solution of
sodium bicarbonate (2 ꢀ 30 mL) and brine solution (50 mL). The organic
layer was dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give crude thiocyanato product. Pure product was
obtained after column chromatography (silica gel, mesh size 60–120,
eluent ethyl acetate–hexane 10:90).
SPECTRAL DATA FOR THIOCYANATO COMPOUNDS
2
-Methyl-4-thiocynatobenzeneamine 2a
ꢁ
[10a]
ꢁ
70–71 C). H NMR (60 MHz, CDCl ): d 2.44
3
1
Solid, mp 70–71 C (lit.
(
(
s, 3H), 3.75 (bs, 2H), 6.43–6.62 (m, 2H), 7.18–7.52 (m, 1H) ppm. IR
ꢂ1
KBr): nmax 3354, 3243, 2145 (-SCN), 1628, 1592, 1492, 1298, 821 cm
.

Thiocyanation of Activated Arenes
2679
2
,6-Dimethyl-4-thiocyanatobenzenamine 3a
ꢁ
[10b]
ꢁ
87–88 C). H NMR (60 MHz, CDCl ): d 2.44
3
1
Solid, mp 85–87 C (lit.
(
2
s, 6H), 3.87 (bs, 2H), 6.62 (s, 1H), 7.22 (s, 1H) ppm. IR (KBr): n
147 (-SCN), 1615, 1592, 1460, 1288 cm
2928,
max
ꢂ1
.
N-Ethyl-4-thiocyanatobenzenamine 4a
ꢁ
[6d]
1
ꢁ
Solid, mp 54–55 C (lit.
ꢂ1
52–53 C). IR (KBr): n
3388, 29755, 2156
max
(
-SCN), 815, 775 cm . H NMR (60 MHz, CDCl ): d ¼ 3.02 (s, 6H),
3
6
.60 (d, J ¼ 8.4 Hz, 2H), 7.40 (d, J ¼ 8.4 Hz, 2H) ppm.
N,N-Dimethyl-4-thiocynatobenzeneamine 5a
ꢁ
[5a]
ꢁ
Solid, mp 72–72 C (lit.
(
72–74 C). IR (KBr): n
3382, 3095, 2159
max
ꢂ1
1
-SCN), 1685, 1465, 1295, 765 cm
.
H NMR (60 MHz, CDCl3):
d ¼ 3.02 (s, 6H), 6.60 (d, J ¼ 8.4 Hz, 2H), 7.40 (d, J ¼ 8.4 Hz, 2H) ppm.
N,N-Diallyl-4-thiocyanatobenzenamine 6a
[
1]
Oil. H NMR (60 MHz, CDCl ): d 3.78–3.97 (m, 4H), 4.96–5.26 (m,
3
4
2
1
6
H), 5.55–6.06 (m, 2H), 6.63 (d, J ¼ 9.0 Hz, 2H), 7.35 (d, J ¼ 9.0 Hz,
H) ppm. IR (KBr): n 3082, 2916, 2148 (-SCN), 1641, 1591, 1504,
238, 811 cm . Elemental analysis calcd. for C H N S: C, 67.79; H,
max
ꢂ1
1
3
14
2
.13; N, 12.16. Found: C, 67.82; H, 6.15; N, 12.18.
N-Benzyl-N-methyl-4-thiocyanatobenzenamine 7a
ꢁ
1
Solid, mp 68–70 C. H NMR (60 MHz, CDCl ): d 3.07 (s, 3H), 4.57
3
(
s, 2H), 6.69 (d, J ¼ 9.0 Hz, 2H), 7.05 (s, 5H), 7.39 (d, J ¼ 9.0 Hz, 2H)
ꢂ1
ppm. IR (KBr): n
Elemental analysis calcd. for C H N S: C, 70.83; H, 5.55; N, 11.01.
3014, 2144 (-SCN), 1599, 1460, 1023, 824 cm
.
max
1
5
14
2
Found: C, 70.85; H, 5.54; N, 10.98.
2
-Methyl-3-thiocyanato-1H-indole 8a
ꢁ
[5c]
ꢁ
1
Solid, mp 101–102 C (lit. 102–103 C). H NMR (60 MHz, CDCl ): d
3
2
.50 (s, 3H), 7.70–7.75 (m, 3H), 7.69–7.64 (m, 1H), 8.56 (bs, 1H) ppm.
3323, 3061, 2152 (-SCN), 1614, 1583, 1408, 1228,
IR (KBr): n
max
ꢂ1
7
41 cm
.

2680
U. S. Mahajan and K. G. Akamanchi
2
-Thiocyanatothiophene 9a
[
7c]
1
Oil (lit. oil). H NMR (60 MHz, CDCl ): d 7.50–8.12 (m, 3H) ppm. IR
3
ꢂ1
(
neat): nmax 3012, 2158 (-SCN), 1412, 1215, 850, 728 cm
.
2
-Methyl-4-thiocyanatophenol 11a
ꢁ
[10c]
ꢁ
71–72 C). H NMR (60 MHz, CDCl ): d 3.24
3
1
Solid, mp 70–72 C (lit.
(
2
s, 3H), 6.14 (brs, 1H), 6.64–7.25 (m, 3H) ppm. IR (KBr): n
3378,
max
ꢂ1
925, 2159 (-SCN), 1597, 1495, 1275, 815 cm
.
1
-Methoxy-4-thiocyanatonaphthalene 12a
ꢁ
[7a]
ꢁ
106–107 C). H NMR (60 MHz, CDCl ): d
3
1
Solid, mp 104–106 C (lit.
4
.08 (s, 3H), 6.71–6.75 (m, 1H), 7.62–8.29 (m, 5H) ppm. IR (KBr):
ꢂ1
nmax 2978, 2152 (-SCN), 1591, 1271, 1063, 807, 771 cm
.
2
-Amino-6-bromobenzothiazol 13a
ꢁ
[10d]
ꢁ
213–214 C). H NMR (60 MHz, CDCl ): d
3
1
Solid, mp 212–213 C (lit.
4
.93–5.31 (bs, 2H), 7.32–7.85 (m, 3H) ppm. IR (KBr): n
3320, 3430,
max
ꢂ1
1
605 cm
.
ACKNOWLEDGMENTS
We sincerely thank the University Grants Commission and All India
Council for Technical Education of India for financial support.
REFERENCES
1. Kelly, T. R.; Kim, M. H.; Certis, A. D. M. Structure correction and synthesis
of the naturally occurring benzothiazinone BMY 40662. J. Org. Chem. 1993,
58, 5855.
2
. (a) Toste, F. D.; Laronde, F.; Still, W. J. Thiocyanate as a versatile synthetic
unit: Efficient conversion of ArSCN to aryl alkyl sulfides and aryl thioesters.
Tetrahedron Lett. 1995, 36, 2949; (b) Grant, M. S.; Snyder, H. R. Thiocyana-
tion of Indole. Some Reactions of 3-Thiocyanoindole. J. Am. Chem. Soc.
1960, 82, 2742.
3
. Zhang, Z.; Liebeskind, L. S. Palladium-catalyzed, copper(I)-mediated
coupling of boronic acids and benzylthiocyanate: A cyanide-free cyanation
of boronic acids. Org. Lett. 2006, 8, 4331.

Thiocyanation of Activated Arenes
2681
4
. (a) Hagen, S. E.; Vara Prasad, J. V. N.; Boyer, F. E.; Domagala, J. M.;
Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Markoski, L. J.; Steinbaugh,
B. A.; Tait, B. D.; Lunney, E. A.; Tummino, P. J.; Ferguson, D.; Hupe,
D.; Nouhan, C.; Gracheck, S. J.; Saunders, J. M.; Vanderroest, S. Synthesis
of 5,6-dihydro-4-hydroxy-2-pyrones as HIV-1 protease inhibitors: The pro-
found effect of polarity on antiviral activity. J. Med. Chem. 1997, 40, 3707;
(
b) Tait, B. D.; Hagen, S.; Domagala, J.; Ellsworth, E. L.; Gajda, C.;
Hamilton, H. W.; Vara Prasad, J. V. N.; Ferguson, D.; Graham, N.; Hupe,
D.; Nouhan, C.; Tummino, P. J.; Humblet, C.; Lunney, E. A.; Pavlovsky, A.;
Rubin, J.; Gracheck, S. J.; Baldwin, E. T.; Bhat, T. N.; Erickson, J. W.;
Gulnik, S. V.; Liu, B. 4-Hydroxy-5,6-dihydropyrones, potent non-peptide
inhibitors of HIV protease. J. Med. Chem. 1997, 40, 3781.
5
. (a) Wu, G.; Liu, Q.; Shen, Y.; Wu, W.; Wu, L. Regioselective thiocyanation
of aromatic and heteroaromatic compounds using ammonium thiocyanate
and oxone. Tetrahedron Lett. 2005, 46, 5831; (b) Yadav, J. S.; Reddy, S. B. V.;
Shubashree, S.; Sadashiv, K. Iodine=MeOH: A novel and efficient reagent
system for thiocyanation of aromatics and heteroaromatics. Tetrahedron Lett.
2004, 45, 2951; (c) Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Reddy,
C. S.; Narsaiah, A.V. Ferric(III) chloride–promoted electrophilic thiocyanation
of aromatic and heteroaromatic compounds. Synthesis 2005, 961.
6
. (a) Toste, F. D.; Stefano, V. D.; Still, I. W. J. A versatile procedure for the
preparation of aryl thiocyanates using N-thiocyanatosuccinimide (NTS).
Synth. Commun. 1995, 25, 1277; (b) Nair, V.; George, T. G.; Nair, L. G.;
Panicker, S. B. A direct synthesis of aryl thiocyanates using cerium(IV)
ammonium nitrate. Tetrahedron Lett. 1999, 40, 1195; (c) Syvret, R. G.; Butt,
K. M.; Nguyen, T. P.; Bulleck, V. L.; Rieth, R. D. Novel process for generat-
ing useful electrophiles from common anions using Selectfluor fluorination
Agent. J. Org.Chem. 2002, 67, 4487; (d) Chakrabarty, M.; Sarkar, S. A
clay-mediated eco-friendly thiocyanation of indoles and carbazoles. Tetrahe-
dron Lett. 2003, 44, 8131.
7
. (a) Kita, Y.; Takada, T.; Mihara, S.; Whelan, B. A.; Tohma, H. Novel and
direct nucleophilic sulfenylation and thiocyanation of phenol ethers using a
hypervalent iodine(III) reagent. J. Org. Chem. 1995, 60, 7144; (b) Kita, Y.;
Takada, Y.; Okuno, T.; Egi, M.; Kiyosei, I.; Kawaguchi, C.; Akai, S. An
efficient p-thiocyanation of phenols and naphtols using a reagent combina-
tion of phenyliodine dichloride and lead(II) thiocyanate. Chem. Pharm. Bull.
1997, 45, 1887; (c) Karande, N. N.; Tiwari, G. B.; Shirodkar, S. G.; Dhoot, B.
M. Efficient and mild oxidative nuclear thiocyanation of activated aromatic
compounds using ammonium thiocyanate and diacetoxyiodobenzene. Synth.
Commun. 2005, 35, 1197.
8
3
. (a) Salgaonker, P. D.; Shukla, V. G.; Akamanchi, K. G. Iodic acid (HIO ) in
combination with tetraethylammonium bromide as a catalyst for selective
and accelerated sulfoxidation. Synth. Commun. 2005, 35, 2805; (b) Patil,
B. R.; Bhusare, S. R.; Pawar, R. P.; Vibhute, Y. B. Iodine and iodic acid:
An efficient reagent combination for iodination of aryl hydroxy ketones. Tet-
rahedron Lett. 2005, 46, 7179; (c) Zolfigol, M. A.; Choghamarani, A. G.;

2682
U. S. Mahajan and K. G. Akamanchi
Shirini, F.; Keypour, H.; Salehzadeh, S. Chemoselective N-nitrosation of
secondary amines under mild and heterogeneous conditions. Synth. Commun.
2001, 31, 359.
9
. (a) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G.
o-Iodoxybenzoic acid- and tetraethylammonium bromide–mediated oxidative
transformation of primary carboxamides to one-carbon dehomologated
nitriles. J. Org. Chem. 2007, 73, 662; (b) Arote, N. D.; Bhalerao, D. S.;
Akamanchi, K. G. Direct conversion of aldehydes to acyl azides using tert-
butyl hypochlorite. Tetrahedron Lett. 2007, 48, 5661; (c) Ramnarayanan,
G. V.; Shukla, V. G.; Akamanchi, K. G. A novel and one step procedure
for preparation of a-bromo-a,b-unsaturated carbonyl compounds. Synlett
2002, 12, 2059; (d) Shukla, V. G.; Salgaonker, P. D.; Akamanchi, K. G. A
mild, chemoselective oxidation of sulfides to sulfoxides using o-iodoxyben-
zoic acid and tetraethylammonium bromide as catalyst. J. Org. Chem.
2003, 68, 5422; (e) Chaudhari, S. S.; Akamanchi, K. G. A mild, chemoselec-
tive, oxidative method for deoximation using Dess–Martin periodinane.
Synthesis 1999, 760; (f) Chaudhari, S. S.; Akamanchi, K. G. Deoximation
using Dess–Martin periodinane: Regeneration of ketones from ketoximes.
Tetrahedron Lett. 1998, 39, 3209.
1
0. (a) Zaboev, S. A.; Kudryavtzev, N. A. Thiocyanogenation of organic
compounds. J. Gen. Chem. (USSR) 1935, 5, 1607; (b) Kissman, H. M.;
Tarbell, D. S.; Williams. 2,2-Diphenyl-3,3-dimethylethylenimine and related
compounds. J. Am. Chem. Soc. 1953, 75, 2959; (c) Kaji, A. Synthesis of
organic thiocyanates II: Synthesis of thiocyanate derivatives of phenols and
naphthols. Nippon Kagaku Zasshi. 1961, 82, 382; (d) Jordan, A. D.; Luo,
C.; Reitz, A. B. Efficient conversion of substituted aryl thioureas to 2-
aminobenzothiazoles using benzyltrimethylammonium tribromide. J. Org.
Chem. 2003, 68, 8693.