Indium-mediated allylation of heteroaryl, benzyl, and cinnamyl thiocyanates: A novel route for 3-(allylsulfanyl)-1H-indoles

Article abstract of DOI:10.1246/cl.2008.1082

Heteroaryl, benzyl, and cinnamyl thiocyanates undergo smooth allylation with allyl bromide in the presence of indium or zinc metal in THF at room temperature to produce the corresponding allyl sulfides in good yields and with high selectivity. Copyright

Full text of DOI:10.1246/cl.2008.1082

1082
Chemistry Letters Vol.37, No.10 (2008)
Indium-mediated Allylation of Heteroaryl, Benzyl, and Cinnamyl Thiocyanates:
A Novel Route for 3-(Allylsulfanyl)-1H-indoles
J. S. Yadav,Ã B. V. Subba Reddy, D. Chandrakanth, and A. V. Hara Gopal
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received July 29, 2008; CL-080735; E-mail: yadavpub@iict.res.in)
Heteroaryl, benzyl, and cinnamyl thiocyanates undergo
smooth allylation with allyl bromide in the presence of indium
or zinc metal in THF at room temperature to produce the corre-
sponding allyl sulfides in good yields and with high selectivity.
5-nitro-, 5-bromo-, and 5-cyano derivatives to furnish the corre-
sponding 3-(allylsulfanyl)indoles (Entries b–k, Table 1). This
method is well tolerated with substrates bearing ester, nitro,
Table 1. Indium-mediated allylation of thiocyanates
Entry
a
Substrate (1)
Substrate (2)
Producta
Time/min
Yield/%b
SCN
The indole nucleus is frequently found in medicinal chemis-
try and is considered a ‘‘privileged scaffold.’’1 In particular, 3-
sulfanylindoles are used as COX-2 inhibitors in medicinal chem-
istry.2 These motifs are very common in various drugs for the
treatment of HIV, obesity, cancer, heart diseases, and aller-
gies.3,4 Thiocyanates have proven to be valuable tools for the
synthesis of a wide range of organo-sulfur compounds.5 Numer-
ous reports in the literature concerning their applications attest
to their growing importance. In particular, aryl thiocyanates
are potential precursors for the synthesis of novel organo-sulfur
compounds.6 Furthermore, aryl thiocyanates can be easily trans-
formed into various sulfur functional groups such as thiophenols
by reduction with lithium aluminum hydride and aryl nitriles/
disulphides by aromatic Grignard reagents.7 Recently, samarium
metal has been utilized for the reductive allylation of alkyl
thiocyanates and diaryl disulfides.8 During the last decade,
indium has emerged as a metal of high potential in organic syn-
thesis because it possesses certain unique properties. Indium
metal is unaffected by air or oxygen at ambient temperatures
and can be handled safely without any apparent toxicity. In
addition, indium exhibits low heterophilicity in organic reactions
and thus oxygen- and nitrogen-containing functional groups are
usually well tolerated by organo-indium reagents.8,9 Moreover,
indium-assisted reactions display low nucleophilicity thus per-
mitting chemoselective transformations of groups of similar
reactivity.10–16 However, there have been no previous reports
on the allylation of heteroaryl thiocyanates using allylindium
bromide.
S
Br
2
87
N
H
N
H
SCN
S
25
20
92
90
b
"
N
H
Me
N
H
Me
SCN
S
c
"
"
N
H
CO2Et
SCN
N
H
CO2Et
S
d
25
15
91
94
N
H
N
H
Et
Et
SCN
Ph
S
e
f
"
"
N
H
Ph
N
H
SCN
S
30
25
88
86
N
N
Ph
Ph
S
SCN
SCN
SCN
g
h
i
"
"
N
N
Me
Me
MeO
O2N
MeO
O2N
S
S
90
85
15
30
N
H
N
H
"
"
N
H
N
H
SCN
SCN
Br
Br
S
j
20
20
87
86
83
N
H
N
H
NC
NC
S
k
l
"
"
N
H
N
H
30
30
S
SCN
SCN
N
N
H
H
S
Br
m
70
75
N
H
N
H
SCN
SCN
SCN
S
30
25
45
n
o
p
Br
In this article, we report a simple and convenient method
for the preparation of 3-(allylsulfanyl)indoles by means of the
allylation of 3-thiocyanatoindoles using indium metal and allyl
bromide. Initially, we attempted allylation of 3-thiocyanatoin-
dole (1) with 2.1 equiv of allyl bromide (2) in the presence of
indium metal. The reaction proceeded smoothly in THF at room
temperature to produce 3-(allylsulfanyl)-1H-indole (3a) in 87%
yield (Scheme 1).
N
N
Ph
S
80
71
Br Ph
N
H
N
H
S
Br
N
H
N
H
SCN
SCN
S
S
78c
73c
30
q
r
Br
N
H
N
H
35
10
This result provided incentive for further study of reactions
with various 3-thiocyanatoindoles such as 2-methyl-, 2-carbo-
ethoxy-, 7-ethyl-, 2-phenyl-, N-benzyl-, N-methyl-, 5-methoxy-,
Br
Ph
Ph
N
H
N
H
s
t
Ph
80
90
SCN
SCN
Ph
S
Br
20
Ph
S
Ph
"
SCN
S
Indium/NH4Cl
THF, rt
aAll products were characterized by NMR, IR, and mass spec-
trometry. Yield refers to pure products after chromatography.
c5–7% ꢀ-adduct was observed by NMR spectra of crude
product.
Br
+
N
N
b
H
H
2
1
3a
Scheme 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.10 (2008)
1083
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SCN
S
Indium/NH4Cl
Br
+
THF, rt, 30 min
N
N
H
H
3m
Scheme 2.
SCN
S-CN
S
S
Indium
Br
Indium
Br
N
N
N
N
H
H
InBr
A
4
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Scheme 3.
bromo, and cyano functionalities (Entries c, i, j, and k, Table 1).
Interestingly, the allylation of 2-thiocyanatopyrrole gave the re-
spective 2-(allylsulfanyl)pyrrole in 83% yield (Entry l, Table 1).
However, treatment of 2-methylindole and N-methylindole
with 2-propynylindium bromide generated in situ from metallic
indium and 2-propynyl bromide in THF over 30 min gave the
2-propynyl sulfides in 70 and 75% yields respectively (Entries
m and n, Table 1, Scheme 2).
5
6
Similarly, benzyl bromide and n-butyl bromide reacted with
3-thiocyanatoindole (1) to furnish the corresponding S-benzyl
and S-butyl derivatives respectively (Entries o and p, Table 1).
However, reaction of 3-thiocyanatoindole with crotyl and cin-
namyl bromides gave ꢁ-adducts as major products (Entries q
and r, Table 1). Next, we examined the reactivity of benzyl
and cinnamyl thiocyanates. Interestingly, these thiocyanates also
underwent smooth allylation with allyl bromide under identical
conditions to provide the corresponding benzyl and cinnamyl al-
lylsulfides respectively in good yields (Entries s and t, Table 1).
This method works well for both electron rich as well as electron
deficient substrates. Both N-protected and unprotected indoles
participated in this reaction (Table 1). This method offers several
advantages such as high conversions, mild reaction conditions,
greater selectivity, cleaner reaction profiles, and operational sim-
plicity. The scope and generality of this process is illustrated
with respect to various indolyl thiocyanates and the results
are presented in Table 1.17 The limitation of this methodology
is that alkyl thiocyantes failed to undergo allylation under these
conditions. Mechanistically, it is known that indium reacts
with allyl bromide to generate allylindium species,9 which
subsequently reacts with indole to give intermediate A.18 The
reaction of intermediate A with allyl bromide would furnish
the desired allyl sulfide (Scheme 3).
In case of alkyl-susbstituted thiocyanates (Entries s and t),
the reaction may proceed via the single-electron-transfer (SET)
process as described previously.8
In summary, we have developed an efficient method for the
preparation of 3-(allylsulfanyl and 2-propynylsulfanyl)indoles
by means of the allylation and 2-propynylation of 3-thiocyana-
toindoles. In addition to its simplicity and mild reaction condi-
tions, this method provides good yields of products with high
selectivity, which makes it a useful and attractive process for
the synthesis of 3-susbtituted indoles.
7
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8
9
10 J. Podlech, T. C. Maier, Synthesis 2003, 633.
11 B. C. Ranu, Eur. J. Org. Chem. 2000, 2347.
12 J. S. Yadav, B. V. S. Reddy, K. S. Reddy, K. B. Reddy,
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Lett. 2001, 42, 6385.
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17 General procedure: A mixture of allyl bromide/2-Propynyl
bromide (2.1 mmol) and indium (2.1 mmol) was stirred in
THF at room temperature for 15–20 min to dissolve the metal.
Then thiocyanate (1 mmol) was added and the reaction stirred
for the appropriate time (Table I). After complete conversion
as indicated by TLC, the reaction mixture was quenched with
aqueous saturated ammonium chloride (10 mL) and extracted
with ethyl acetate (3 Â 10 mL). The combined organic extracts
were dried over anhydrous Na2SO4, and concentrated in va-
cuo. The resulting product was purified by column chromatog-
raphy on silica gel (Merck, 100–200 mesh, ethyl acetate–
hexane, 1:7) to afford the pure product (Caution: Work-up to
be carried out with utmost care to avoid possible toxicity of
indium cyanide towards skin. See Supporting Information.19
18 J. S. Yadav, B. V. S. Reddy, P. M. Reddy, C. Srinivas,
Tetrahedron Lett. 2002, 43, 5185.
References and Notes
1
R. J. Sundberg, Indoles, Academic Press, San Diego, 1996;
G. W. Gribble, J. Chem. Soc., Perkin Trans 1 2000, 1045;
S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873; G. R.
19 Supporting Information is also available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Published on the web (Advance View) September 20, 2008; doi:10.1246/cl.2008.1082