1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane Bis(tetrafluoroborate) as Novel and Versatile Reagent for the Rapid Thiocyanation of Indoles, Azaindole, and Carbazole

Article abstract of DOI:10.1246/cl.2008.652

Selectfluor is found to catalyze efficiently the electrophilic thiocyanation of indoles and pyrrole with ammonium thiocyanate under mild and neutral conditions to produce the corre-sponding 3-indolyl and 2-pyrrolyl thiocyanates, respectively, in excellent

Full text of DOI:10.1246/cl.2008.652

652
Chemistry Letters Vol.37, No.6 (2008)
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane Bis(tetrafluoroborate)
as Novel and Versatile Reagent for the Rapid Thiocyanation of Indoles,
Azaindole, and Carbazole
J. S. Yadav,ꢀ B. V. Subba Reddy, and Y. Jayasudhan Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received January 30, 2008; CL-080107; E-mail: yadavpub@iict.res.in)
SelectfluorÔ is found to catalyze efficiently the electrophilic
on the fact that F-TEDA-BF4 has considerable oxidative power,
thiocyanation of indoles and pyrrole with ammonium thiocya-
nate under mild and neutral conditions to produce the corre-
sponding 3-indolyl and 2-pyrrolyl thiocyanates, respectively,
in excellent yields with high selectivity. This method is effective
even with azaindole and carbazole while many of reported
procedures failed to produce thiocyanates from azaindole.
one of the strongest in the family of N–F reagents. But investi-
gations taking advantage of this property are still scarce.9
Furthermore, there have been no examples on the use of
SelectfluorÔ for the electrophilic thiocyanation of indoles.
In this article, we report a simple, convenient, and
efficient protocol for the thiocyanation of N-heterocycles using
SelectfluorÔ in acetonitrile. Initially, we attempted the electro-
philic thiocyanation of indole (1) with 1 equiv of ammonium
thiocyanate (2) using a stoichiometric amount of SelectfluorÔ.
The electrophilic thiocyanation of aromatics and heteroaro-
matics is one of the most important carbon–heteroatom bond-
forming reactions in organic synthesis.1 Aryl and heteroaryl
thiocyanates are useful intermediates in the synthesis of sulfur-
containing heterocycles.2 They are useful intermediates for
drugs and pharmaceuticals.2b They can be easily transformed in-
to various sulfur-containing functional groups.3 The thiocyanate
functionality is useful as a masked sulfanyl group. Therefore, the
direct thiocyanation of aromatic systems is of prime importance.
As a result, several methods have been developed for the thio-
cyanation of arenes using a variety of reagents under certain con-
ditions.4 However, a few reagents such as N-halosuccinimides,
ceric ammonium nitrate, acidic K10 clay, iodine/methanol,
and oxone have been applied for the thiocyanation of indoles.5,6
However, these methodologies suffer from drawbacks such
as the use of strong oxidizing agents, toxicity of metal thiocya-
nates, low yields of products in some cases, less availability or
hard preparation of precursors and the formation of mixtures
of products as a result of bisthiocyanation especially in case of
pyrroles. In addition, many of these methods fail to induce
electrophilic thiocyanation on azaindole. In view of the versatil-
ity of thiocyanate group in the field of drugs and pharmaceuti-
cals, the development of simple, convenient, and highly efficient
approaches are desirable. SelectfluorÔ [1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)]
has recently been introduced commercially as a user-friendly
electrophilic fluorinating reagent (Figure 1).7
Table 1. Thiocyanation of N-heterocycles with ammonium
thiocyanate using SelectfluorÔ
Entry
Substrate
Producta
Time/min
Yield%b
SCN
a
b
10
10
95
N
H
N
H
SCN
Me
92
Me
N
H
N
H
SCN
c
d
12
10
94
93
N
N
H
Et
H
Et
SCN
O2
N
O2N
N
H
N
H
SCN
NC
Br
NC
Br
e
f
10
10
92
93
N
H
N
H
SCN
N
H
N
H
SCN
MeO
MeO
g
h
i
9.0
15
96
89
94
85
N
H
N
H
SCN
Ph
Ph
N
H
N
H
SCN
12
N
N
N
N
Ph
Ph
SCN
Ph
j
15
Ph
Me
Me
It is a commercially available, stable, nonvolatile, nonhy-
groscopic, and easy to handle solid and is more widely used
for site-selective fluorination of a variety of carbonyl com-
pounds. Besides its fluorinating ability, it is also recognized as
a convenient mediator of several ‘‘fluorine free’’ functionaliza-
tion of organic compounds.8 These kinds of reactions are based
SCN
k
l
15
10
88
92
N
H
N
N
N
H
SCN
N
H
N
H
m
10
98
N
H
SCN
N
H
NCS
NCS
n
o
15
20
82
78
+
Cl
N
2BF4
+
NEt2
NEt2
-
NHEt
NHEt
N
aAll products were characterized by 1H NMR, IR, and mass
spectrometry. Yield refers to pure products after chromatogra-
phy.
F
b
Figure 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.6 (2008)
653
and the results are presented in Table 1. The redox potentials of
indole and SelectfluorÔ are ꢁ1:050 and ꢁ0:296 V, respective-
ly.10 Mechanistically, the reaction may proceed via the electro-
philic substitution of indole by in situ generated thiocyanogen
(þSCN) from SelectfluorÔ and ammonium thiocyanate
(Scheme 3).11
SCN
SelectfluorTM
NH4SCN
+
N
N
CH3CN, rt
H
H
1
2
3a
Scheme 1.
In conclusion, SelectfluorÔ has proved to be an effective
reagent for the electrophilic thiocyanation of N-heterocycles un-
der extremely mild and neutral conditions. In addition to its sim-
plicity and efficiency, this method produces monothiocyanated
products in excellent yields in short reaction times. This method
provides the direct access to a wide range of potentially valuable
biologically well-defined heteroaryl thiocyanates. This method
can be used for the thiocyanation of even deactivated indoles
in an efficient manner.
SelectfluorTM
CH3CN, rt
SCN
NH4SCN
+
N
N
H
H
1l
2
3l
Scheme 2.
CH3CN
rt
+
+
NH4SCN
[ SCN]
NH4F
Selectfluor (F )
+
+
References and Notes
1
J. L. Wood, Organic Reactions, Wiley, New York, 1967,
Vol. III, p. 240.
SCN
CH3CN
rt
2
a) A. W. Erian, S. M. Sherif, Tetrahedron 1999, 55, 7957.
b) R. G. Guy, in The Chemistry of Cyanates and Their Thio
Derivatives, ed. by S. Patai, John Wiley & Sons, New York,
1977, Part 2, Chap. 18, p. 819.
+
[ SCN]
+
N
N
H
H
Scheme 3.
3
4
5
a) F. D. Toste, F. Laronde, W. J. Still, Tetrahedron Lett.
1995, 36, 2949. b) M. S. Grant, H. R. Snyder, J. Am. Chem.
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The reaction went to completion within 10 min. at room temper-
ature and the product, 3-thiocyanatoindole (3a), was obtained
in 95% yield (Entry a, Table 1 and Scheme 1).
Encouraged by this result, we turned our attention to various
indoles. Interestingly, several substituted indoles such as 2-
methyl-, 7-ethyl-, 5-nitro-, 5-cyano-, 5-bromo-, 5-methoxy-,
and 2-phenylindoles reacted rapidly with ammonium thiocya-
nate to afford the corresponding 3-thiocyanatoindole derivatives
(Entries b–h, Table 1). In addition, N-protected indoles such as
N-benzyl- and N-ethyl derivatives also participated effectively
in this reaction (Entries i and j, Table 1). It is noteworthy to men-
tion that less reactive 7-azaindole also gave the corresponding 3-
thiocyanato-7-azaindole in 88% yield (Entry k, Table 1) while
most of the reported procedures failed to induce an electrophilic
thiocyanation on azaindole.5,6 Furthermore, 9H-carbazole also
reacted well under similar conditions to give 3-thiocyanato-
9H-carbazole (Entry l, Table 1, Scheme 2).
In case of carbazole, monothiocyanation took place at the 3-
position of benzene ring. Like indoles, pyrrole was also easily
transformed into the monothiocyanatopyrrole. In case of pyrrole,
the substitution took place at 2-position to produce 2-thiocya-
natopyrrole (Entry m, Table 1). No bisthiocyanation was
observed in case of pyrrole. Furthermore, N-alkylanilines
also underwent smooth thiocyanation under these reaction
conditions (Entries n and o, Table 1).12
6
7
8
9
In all cases, the reactions proceeded rapidly at room temper-
ature with high regioselectivity. As solvent, acetonitrile ap-
peared to give the best results. No fluorination of indole was ob-
served under the reaction conditions. The products were charac-
terized by 1H NMR, IR, and mass spectrometry and also by com-
parison with authentic samples.5,6 The scope and generality of
this process is illustrated with respect to various N-heterocycles
10 a) P. Y. Toullec, C. Bonaccorsi, A. Mezzetti, A. Togni, Proc.
Nal. Acad. Sci. U.S.A. 2004, 101, 5810. b) G. Wu, Q. Liu,
Y. Shen, W. Wu, L. Wu, Tetrahedron Lett. 2005, 46, 5831.
11 R. G. Syvret, K. M. Butt, T. P. Nguyen, V. L. Bulleck,
R. D. Rieth, J. Org. Chem. 2002, 67, 4487.
12 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/.
Published on the web (Advance View) May 24, 2008; doi:10.1246/cl.2008.652