Yttrium triflate-catalyzed efficient chemoselective S-benzylation of indoline-2-thiones using benzyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.11.163

A highly efficient yttrium triflate-catalyzed chemoselective S-benzylation of indolin-2-thiones using variously substituted benzyl alcohols has been developed for the synthesis of indole-based sulfides. This procedure presents a greener approach for the s

Full text of DOI:10.1016/j.tetlet.2010.11.163

Tetrahedron Letters 52 (2011) 684–687
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Yttrium triflate-catalyzed efficient chemoselective S-benzylation
of indoline-2-thiones using benzyl alcohols
⇑
Mukund Jha , Oro Enaohwo, Stephanie Guy
Department of Biology and Chemistry, Nipissing University, North Bay, ON, Canada P1B 8L7
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient yttrium triflate-catalyzed chemoselective S-benzylation of indolin-2-thiones using var-
iously substituted benzyl alcohols has been developed for the synthesis of indole-based sulfides. This pro-
cedure presents a greener approach for the synthesis of S-alkylated indoles. The reaction condition is
amenable to primary, secondary, and tertiary benzylic alcohols as the benzyl group donors.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 October 2010
Revised 24 November 2010
Accepted 30 November 2010
Available online 5 December 2010
Keywords:
S-Benzylation
Chemoselective
Indoline-2-thione
Benzyl alcohol
Rare earth metal triflates
Yttrium triflate
Indole derivatives possess a diverse array of biological and
pharmacological activities.1 Owing to their high biological impor-
tance, development of the efficient syntheses of indole derivative
continues to attract significant attention of synthetic chemists.2
Among various indole derivatives, indole-based sulfides and
sulfoxides are of particular interest because of their medicinal
properties and potential application in synthetic chemistry as
intermediates.3–11 Biological activities such as antiviral,3 HIV-1 re-
verse transcriptase inhibitors,4 protein tyrosine kinase inhibitor,5
antitumor,6 antihyperlipidemic,7 and antiulcer8 have been re-
ported from indole-conjugated sulfides and sulfoxides (Fig. 1). On
the other hand, sulfides can be used as alkylating9 and sulfenylat-
ing10 agents whereas optically active sulfoxides can be used as chi-
rality inducing agents9,11 and, therefore, may find applications in
synthetic chemistry.
The benzylation reaction is frequently used in synthetic chem-
istry as a tool for the protection of heteroatoms (N, O and S). The
ease with which the benzyl group can be introduced and removed
makes this strategy quite valuable for synthetic chemists.12 Benzyl
halides, which are toxic, carcinogenic, and lachrymose,13 are most
commonly used as benzyl donors for the benzyl protection reac-
tions. Several other reagents, which use activated benzyl alcohols,
have been developed for the benzylation of heteroatoms. For
example, 2-benzyloxy-1-methylpyridinium triflate efficiently alky-
lates alcohols under mild conditions,14 oligomeric sulfonate es-
ters,15 and oligomeric benzyl phosphates16 have been shown to
benzylate amines, benzylation of aromatic amines using benzyl
alcohols is efficiently catalyzed by magnetite17 and ben-
zyldimethylsulfonium salts have been used for the benzylation of
alcohols and thiols.18
Recently, we have reported the first example of the S-benzyla-
tion reaction using benzyl alcohols as an electrophile source in
the presence of BF3 etherate.19 In this finding, treatment of indo-
line-2-thiones with aromatic substituted primary benzyl alcohols
in the presence BF3 etherate in aprotic solvents, resulted in the
chemoselective formation of 2-(benzylthio)-1H-indoles in
NHPh
OH
O
S
N
N
S
N
S
Me
Me
O
NHPh
Ph
S
F2HCO
OMe
O
NH2
OMe
N
S
O
N
H
H
N
O
⇑
Corresponding author.
E-mail address: mukundj@nipissingu.ca (M. Jha).
Figure 1. Representative examples of biologically active indole-based sulfides and
sulfoxides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.163

M. Jha et al. / Tetrahedron Letters 52 (2011) 684–687
685
excellent yields. The indoline-2-thione (1) moiety has three
potential nucleophilic sites, namely the 1-N, the S of thione group
in the thiol form and the 3-C. Among them, S is the most nucle-
ophilic and results in exclusive formation of S-benzylated prod-
ucts in the reaction. To systematically conclude our study on
S-benzylation of indoline-2-thiones, we have screened a series
of rare earth metal triflates as potential catalysts for the S-benzy-
lation of indoline-2-thiones. We wish to now disclose that rare
earth metal triflates can also efficiently catalyze the chemoselec-
tive S-benzylation of indoline-2-thione using benzylic alcohols.
After logical and systematic screening, we have identified yttrium
triflate (Y(OTf)3) as a highly efficient and environmentally friendly
catalyst to catalyze this transformation. The substrate scope is ex-
panded by using benzyl alcohols with a higher degree of substitu-
tion on the benzylic carbon to synthesize new S-benzylated
analogs and to further obtain support for the proposed reaction
mechanism.
The Lewis acid complex BF3 etherate is an effective catalyst
widely used for a variety of organic transformations, among
them the most common being C-alkylation.20 Indoline-2-thione
(1), which can be readily obtained from indolin-2-one,21 is a use-
ful precursor for the synthesis of indole based heterocycles. We
are actively involved in exploring the chemistry around the in-
dole nucleus to develop useful synthetic methodologies to access
indole-based novel molecular structures.19,22 In our preliminary
report,19 we noted that the reaction of indoline-2-thiones (1–3)
with arylmethanols in the presence of BF3 etherate in aprotic sol-
vents resulted in the chemoselective formation of S-benzylated
indoles. The reactions progressed quite efficiently in the case of
electron rich benzyl alcohols. 4-Nitrobenzyl alcohol was found
to be inert toward the benzylation reaction under similar condi-
tions. Our results support the involvement of benzyl carbocations
in this protocol. Benzyl alcohols upon reaction with the Lewis
acid BF3 etherate lead to the formation of resonance-stabilized
benzyl carbocation intermediates.23 Subsequently, a nucleophilic
attack of the thiol tautomers of the indoline-2-thiones results
in the formation of the S-benzylated products. This is further
substantiated by the observation that benzyl alcohols capable
of forming resonance stabilized carbocations give faster and effi-
cient reactions while those with lacking stabilizing groups give
slower reactions or do not react at all. Further, these resonance
stabilized soft electrophiles (carbocations) react chemoselectively
with soft nucleophile –SH,24 in the presence of other nucleophilic
centers such as N-1 and C-3 of the indole nucleus. The treatment
of indolin-2-one (as opposed to indoline-2-thione) with benzyl
alcohol under similar conditions did not yield any product; this
highlights the unique nucleophilicity of S in indoline-2-thiones
versus the O at C-2 in indolin-2-one. All these observations fur-
ther accentuate the involvement of resonance-stabilized carbo-
cation intermediates in this highly selective benzylation in
electron rich species.
Although a versatile catalyst,20 BF3 etherate is not a reagent of
choice owing to its corrosive and fuming nature. In the previous
report,19 2 equiv of BF3 etherate was used without optimization
to carry out the synthesis of indole sulfides. It should be noted
that a molecule of water is formed as a by-product in the
reaction. Also, most main group and d-block Lewis acid halides
are water sensitive and produce catalytically less effective
hydroxides.25 We first decided to optimize the best catalytic con-
dition for the reaction under investigation. For the optimization
experiments, benzhydrol and N-methylindoline-2-thione (3) were
chosen as the model reactants. Molecular sieve (4 Å) was intro-
duced in the reaction to absorb the liberated water. Using lower
molar ratios than originally employed, we have now established
that 20 mol % of BF3 etherate is as effective as using 200 mol %
(Table 1, entries 1–3). We had also disclosed previously19 that
BF3 etherate can be substituted with 5–20 mol % of p-toluenesul-
fonic acid (p-TSA) to perform the same reactions but the rate of
the reaction and the product yield was found to be considerably
lower. Use of 20 mol % of p-TSA under optimization conditions
yielded only 58% of the product (Table 1, entry 4). Further in-
crease in the concentration of p-TSA was not appealing for a cat-
alytic transformation. Rare earth metal triflates are known to be
effective, mild, and relatively less toxic Lewis acids with consider-
ably higher water stability.26 This prompted us to screen a series
of rare earth metal triflates as Lewis acid catalysts capable of
effectively catalyzing the reaction under investigation with low
catalyst loading. The results are presented in Table 1. As it can
be clearly seen, three of the four rare earth metal triflates
(Sc(OTf)3, Eu(OTf)3 and Y(OTf)3), used were as effective as BF3
etherate in catalyzing the reaction under question. Y(OTf)3 was
found to be most effective at 20 mol %;27 however, use of a lower
concentration led to lower yields even after longer reaction time
(Table 1).
Having identified an efficient catalyst and an optimal reaction
condition, we set out to further study the substrate scope where
we employed a variety of benzyl alcohols with varying bulk (pri-
mary, secondary, and tertiary) on the benzylic carbon. The results
are presented in Table 2. The isolated yields of the desired products
ranged from 76% to 93%. It is noteworthy that the reaction condi-
tion is not only amenable to alcohols having higher degree of sub-
stitutions but also to heteroaromatic 2-furanyl methanol (Table 2,
Table 1
Screening of potential catalysts for the S-benzylation of indoline-2-thiones
Catalyst
Dioxane
Molecular sieves (4Å)
Ph
S
Ph
HO
Ph
S
+
N
100 °C
N
Ph
4
3
Entry
Catalyst
Catalyst (mol %)
Reaction time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
BF3 etherate
BF3 etherate
BF3 etherate
p-TSA
La(OTf)3
Sc(OTf)3
Eu(OTf)3
Y(OTf)3
100
50
20
20
20
20
20
20
10
5
1
1
1.5
2
2
1
1
1
3
88
81
84
58
55
88
79
91
71
68
Y(OTf)3
Y(OTf)3
10
3

686
M. Jha et al. / Tetrahedron Letters 52 (2011) 684–687
Table 2
Yttrium triflate-catalyzed chemoselective S-benzylation of indoline-2-thiones
R4 R3
R2
S
20 mol% Y(OTf)3
Dioxane
HO
R4
R3
S
Molecular sieves (4Å)
+
N
N
R
R
°
R2
100 C, 1h
R1
R1
1 R, R1 = H
R = Cl, R = H
R = H, R = CH3
1
4-14
2
3
1
Entry
1
Substrate
Benzyl alcohol
Product
Isolated yield (%)
76
OH
O
O
O
1
S
N
H
5
OH
O
2
3
4
3
1
2
89
90
78
S
6
N
OH
Ph
Ph
S
N
H
7
OH
Ph
Ph
S
N
H
Cl
8
OH
5
6
7
1
2
3
93
88
92
S
N
H
9
OH
OH
S
10
N
H
Cl
S
11
N
OH
Ph
Ph
Ph
Ph
Ph
8
9
1
2
3
3
85
81
91
87
S
4
N
H
OH
Ph
Ph
Ph
S
12
N
H
Ph
Cl
OH
Ph
Ph
Ph
Ph
10
11
S
N
N
13
OH
Ph
Ph
Ph Ph
Ph
S
14
entries 1 and 2). It has been suggested that rare earth metal
triflate-catalyzed alkylation using benzylic alcohols proceeds via
benzylic carbocations.28,29 In agreement with these observations
and our previous results,19 formation of products in Table 2 further

M. Jha et al. / Tetrahedron Letters 52 (2011) 684–687
687
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support the involvement of stabilized carbocations as reaction
intermediates.
In conclusion, we have devised a general chemoselective S-ben-
zylation reaction of indoline-2-thiones using benzyl alcohols cata-
lyzed by Lewis acids under mild conditions. The optimization of
reaction conditions led to the discovery of commercially available
solid Y(OTf)3 as an efficient, inexpensive, and environmentally be-
nign catalyst over previously reported BF3 etherate for this trans-
formation. The reaction condition required relatively low catalyst
loading (20 mol %) compared to BF3 etherate in the previous report.
Furthermore, benzyl alcohols with varying degree of substitutions
at benzylic position reacted quite effectively with indolin-2-
thiones under optimized reaction conditions, thus expanding the
reaction scope substantially. Mechanistically, the exclusive
formation of S-benzylated products in all the cases supports the
involvement of resonance stabilized benzylic carbocation as the
reaction intermediate.
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Financial support from Nipissing University (M.J.) and Ontario
Work Study Program Nipwork (O.E.) is gratefully acknowledged.
We would also like to thank Acadia University for granting access
to their analytical facility.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.163.
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27.
A representative synthetic procedure for yttrium-catalyzed S-benzylation
reaction: Synthesis of 2-(1-phenylethylthio)-1H-indole (7): indoline-2-thione
(1.0 mmol), 1-phenylethanol (1.1 mmol), Y(OTf)3 (0.2 mmol, 20 mol %) and
molecular sieves (4 Å, 50 mg) were taken into dioxane (2 mL). The reaction
mixture was heated at 100 °C for 1 h. The excess of dioxane was removed
under vacuum and the residue was subjected to flash column
chromatography (silica gel, hexanes/ethyl acetate, 90:10) to give 2-(1-
phenylethylthio)-1H-indole (7) as light green solid. Melting point: 68–71 °C.
1H NMR (300 MHz, CDCl3): d 7.71 (br s, 1H, D2O exchangeable), 7.60 (d,
J = 7.8 Hz, 1H), 7.32–7.11 (m, 8H), 6.66 (s, 1H), 4.29 (q, J = 7.0 Hz, 1H), 1.70 (d,
J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 143.7, 137.5, 128.9, 128.7, 127.8,
127.6, 123.1, 120.8, 120.4, 111.3, 111.0, 49.9, 22.1. FTIR mmax (KBr): 2970,
1683, 1669, 1456, 752 cmÀ1
.
ESI-HRMS (amu): calcd C16H14NS [MÀH]À:
252.0852; found [MÀH]À: 252.0842.
28. Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68,
9340–9347.
29. Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. J. Org. Chem. 1997, 62,
6997–7005.