Chemoselective S-benzylation of indoline-2-thiones using benzyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2009.10.050

Indoline-2-thiones were chemoselectively S-benzylated using a variety of benzyl alcohols by boron trifluoride etherate-catalyzed reactions. The aryl substituent effect on the reactivity of the benzyl alcohols toward S-benzylation is also discussed.

Full text of DOI:10.1016/j.tetlet.2009.10.050

Tetrahedron Letters 50 (2009) 7184–7187
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Tetrahedron Letters
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Chemoselective S-benzylation of indoline-2-thiones using benzyl alcohols
*
Mukund Jha , Oro Enaohwo, Ashley Marcellus
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:
Indoline-2-thiones were chemoselectively S-benzylated using a variety of benzyl alcohols by boron tri-
fluoride etherate-catalyzed reactions. The aryl substituent effect on the reactivity of the benzyl alcohols
toward S-benzylation is also discussed.
Received 12 August 2009
Revised 5 October 2009
Accepted 8 October 2009
Available online 29 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
S-Benzylation
Chemoselective
Indoline-2-thione
Benzyl alcohol
Boron trifluoride etherate
Substituted indoles constitute a vast number of synthetic and
naturally occurring compounds that demonstrate a diverse array
of biological and pharmacological activities.1 In the pursuit of
developing novel therapeutic agents, chemists often use an indole
core as the backbone to advance biological activity.2 Sulfur con-
taining indole-based molecules have a special place among biolog-
ically active medicinal agents. For instance, indomethacin (1), a
nonselective inhibitor of cyclooxygenase (COX) 1 and 2, is a non-
steroidal anti-inflammatory drug (NSAID). The extensive struc-
ture–activity relationship studies around 1 led to the development
of sulindac (2), a sulfur containing analog of 1, which is also an
effective NSAID.3 Similarly, 5-chloro-3-(phenylsulfonyl)indole-2-
carboxamide (3) and related compounds were shown to be highly
potent antiviral agents and HIV-1 reverse transcriptase inhibitors.4
Dobrusin et al. reported indole disulfide 4 to display potent protein
tyrosine kinase inhibitory and antitumor activity.5 Miura et al. de-
scribed antihyperlipidemic activity from indole sulfides such as 5.6
The indole sulfoxide 6 and related compounds were shown to have
antiulcer activity (Fig. 1).7 In addition to these, several other inter-
esting biological activities have been reported from sulfur contain-
ing indole derivatives.8
producing epoxides.9 Sulfoxides, on the other hand may be chiral
and may have a great value in asymmetric syntheses.9,10 Recently,
Majumdar et al. reported that thiophenol-mediated radical cycliza-
tion of indole sulfides regioselectively produce indole-annulated
sulfur heterocycles.11 Thus, the development of efficient and practi-
cal syntheses of sulfides and sulfoxides are of great significance.
The Lewis acid complex boron BF3 etherate is an effective cata-
lyst widely used for a variety of organic transformations, among
them the most common being C-alkylation.12–19 In 1974, Jain
et al. had reported BF3 etherate-promoted C-prenylation of the
phloroglucinol nucleus.20 Subsequently, BF3 etherate complex
was shown to catalyze C-benzylation of aromatic systems using
benzyl alcohols.21 While the use of BF3 etherate in aromatic C-
alkylation is well documented, its use in heteroatom alkylation is
not reported. Furthermore, strategies in organic synthesis employ
frequent use of protection of heteroatoms such as nitrogen, oxygen
and sulfur using benzyl groups. Commonly used benzyl donors for
benzyl protection are benzyl halides which are toxic, carcinogenic
and lachrymose.22
Our laboratory is actively involved in exploring the chemistry
around the indole nucleus to develop useful synthetic methodolo-
gies to access indole-based novel molecular structures. In an at-
tempt to C-alkylate the indoline-2-thione nucleus at 3-position
using BF3 etherate and benzyl alcohol, we discovered that a
chemoselective S-benzylation had taken place in an excellent yield.
Also, to the best of our knowledge, this is the first example of S-
benzylated sulfide preparation using benzyl alcohol as an electro-
phile source. Herein, we report a systematic study on chemoselec-
tive S-benzylation of indoline-2-thiones catalyzed by BF3 etherate
using a variety of benzyl alcohols.
Besides possessing diverse biological activities, sulfur containing
compounds, in particular sulfides and sulfoxides, are of great impor-
tance in synthetic chemistry. The sulfonium salts obtained from
highly nucleophilic sulfides serve as strong alkylating agents.9
Base-mediated S-ylide formations play an important role in methy-
lene transfer to alkenes yielding cyclopropanes or to carbonyls
* Corresponding author.
E-mail address: mukundj@nipissingu.ca (M. Jha).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.050

M. Jha et al. / Tetrahedron Letters 50 (2009) 7184–7187
7185
Figure 1. The chemical structures of indomethacin (1) and representative biologically active indole-based sulfides and sulfoxides.
For the purpose of substrate variability, three indoline-2-thione
analogs namely unsubstituted indoline-2-thione (7), 6-chloroindo-
line-2-thione (8), and N-methylindoline-2-thione (9) were se-
lected. The indoline-2-thiones 7–9 were synthesized from
corresponding indolin-2-ones using a previously reported meth-
od.23 Six different benzyl alcohols (Table 1) with varying steric
and electronic properties were chosen as benzyl group donors.
These benzyl alcohols were selected to thoroughly examine the ef-
fect of substitution on the benzylation reaction. The benzyl alco-
hols used were either obtained from commercial sources or were
synthesized from corresponding aldehydes using literature proce-
dure. The reactions of indoline-2-thiones and benzyl alcohols were
carried out in aprotic solvents (dichloromethane, chloroform or
1,4-dioxane) in presence of two molar equivalents of BF3 ether-
ate.24 The results of the benzylation reactions summarized in Table
1 indicate that chemoselective S-benzylation occurred in almost all
cases, except for 4-nitrobenzyl alcohol (entries 13 and 14). The
reactions were unaffected by the type of thiones used, but were
profoundly affected by the type of substituent present on the ben-
zyl alcohols. For example, benzyl alcohols possessing electron-
donating groups such as –OMe and –OCH2O– reacted quite rapidly
with indoline-2-thiones in the presence of BF3 etherate at room
temperature in dichloromethane (Table 1, entries 1–5). The reac-
tions were complete within 0.5 h and the corresponding S-benzy-
lated products were obtained in excellent yields. The time
required for the completion of the reaction with benzyl alcohols
Table 1
Boron trifluoride etherate-catalyzed chemoselective S-benzylation of indoline-2-thiones
Entry
Indoline-2-thione
Benzyl alcohol R00
Solvent
Reaction time (h)
Product
Yield (%)
Melting point (°C)
a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
16e
7
8
9
7
8
7
8
7
8
7
8
9
7
8
7
7
4-OMe
4-OMe
4-OMe
3,4-OCH2O
3,4-OCH2O
2-OH
2-OH
4-OH
4-OH
H
H
H
NO2
NO2
4-OMe
4-OMe
CH2Cl2
0.5
0.5
0.5
0.5
0.5
2
10 R = R0 = H, R00 = 4-OMe
11 R = H, R0 = Cl, R00 = 4-OMe
12 R = Me, R0 = H, R00 = 4-OMe
13 R = R0 = H, R00 = 3,4-OCH2O
14 R = H, R0 = Cl, R00 = 3,4-OCH2O
15 R = R0 = H, R00 = 2-OH
16 R = H, R0 = Cl, R00 = 2-OH
17 R = R0 = H, R00 = 4-OH
18 R = H, R0 = Cl, R00 = 4-OH
19 R = R0 = R00 = H
88
90
85
90
87
84
82
62
67
75
78
72
—
69–70
137–139
76–78
85–86
100–102
94–96
131–133
114–121
133–135
119–120
110–115
Oil
a
CH2Cl2
a
CH2Cl2
a
CH2Cl2
a
CH2Cl2
a
CH2Cl2
a
CH2Cl2
2
Dioxanea
12
12
24
24
24
72c
72c
24
24
Dioxanea
b
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
b
20 R = R00 = H, R0 = Cl
b
21 R = Me, R0 = R00 = H
No reaction
No reaction
10 R = R0 = H, R00 = 4-OMe
10 R = R0 = H, R00 = 4-OMe
b
—
—
68–70
68–70
b
—
70
67
b
b
a
b
c
The reaction mixture was stirred at room temperature.
The reaction mixture was refluxed.
The reaction mixture was monitored for 72 h by TLC.
5 mol % p-TSA-catalyzed reaction.
d
e
20 mol % p-TSA-catalyzed reaction.

7186
M. Jha et al. / Tetrahedron Letters 50 (2009) 7184–7187
containing an electron-donating hydroxyl group increased to 2 h at
room temperature (Table 1, entries 6 and 7). It was interesting to
note that o-hydroxybenzyl alcohol, which has intramolecular
hydrogen bonding, reacted with thiones in dichloromethane with-
out any problem, whereas p-hydroxybenzyl alcohol had a poor sol-
ubility in dichloromethane and the reaction appeared to proceed
slowly. To overcome the challenges posed by solubility, dioxane
was used as the reaction solvent and thin layer chromatography
(TLC) analysis revealed that the reaction was complete in 12 h (Ta-
ble 1, entries 8 and 9). Additionally, the use of o and p-hydroxyben-
zyl alcohols in the S-benzylation highlights the synthetic utility of
BF3 etherate mediated sulfide formations. Additional protection/
deprotection steps for the hydroxyl group are not necessary for
the S-benzylation to take place. Also, as previously stated, benzyl
alcohols are known to C-benzylate phenols in the presence of BF3
etherate; we did not isolate any products with multiple benzyla-
tion or oligomerization under the applied conditions. This suggests
that the reaction is kinetically controlled and S-benzylation over-
powers possible competing reactions. A significant slowdown in
the reaction rate was observed when unsubstituted benzyl alcohol
was used (Table 1, entries 10–12). In order to drive the reaction to
completion additional heating was required. Refluxing the reaction
mixtures in chloroform for 24 h resulted in corresponding S-benzy-
lated products with good yields (Table 1, entries 10–12). Finally, p-
nitrobenzyl alcohol was found to be completely inert toward the
BF3 etherate-catalyzed S-benzylation of indoline-2-thiones (Table
1, entries 13 and 14). The refluxing of p-nitrobenzyl alcohol with
indoline-2-thiones and BF3 etherate in chloroform up to 72 h did
not afford any product and the starting compounds were recovered
from the reaction mixture.
(entry 12) did not afford any multiple benzylation product(s) and
only S-benzylated product 21 was recovered from the reaction
mixture in 70% yield. However, we are continuing to investigate
the potential of multiple alkylation and the results would be re-
ported in the future.
Next, the catalyst BF3 etherate was substituted with p-toluene-
sulfonic acid (p-TSA) in efforts to develop more environmentally
benign reaction conditions (Table 1, entries 15 and 16). When 4-
methoxybenzyl alcohol was treated with indolin-2-thione (7) in
the presence of 5 mol % of p-TSA, the S-benzylated product 10
was obtained. However, when compared to BF3 etherate reaction
conditions (Table 1, entry 1), the progress of the reaction was sig-
nificantly slower. The reaction mixture had to be refluxed in chlo-
roform for 24 h to give 10 in nearly 70% yields. Similar result was
obtained when the concentration of p-TSA was increased to
20 mol %. The S-benzylation mediated by p-TSA appears promising
and we are currently investigating these results in detail. Prospects
of other environmentally-benign catalysts will also be studied.
In conclusion, we have described the first example of chemoselec-
tive S-benzylation of indoline-2-thiones using benzyl alcohols cata-
lyzed by BF3 etherate under mild conditions. Benzyl alcohols
possessing electron-donating groups reacted quite efficientlyat room
temperature with indoline-2-thiones. The unsubstituted benzyl alco-
hol was slow to react and required additional heating whereas the
electron-withdrawing –NO2 group bearing alcohol was inert toward
these nucleophilic substitution reactions. It is worthwhile to mention
that under these reaction conditions o and p-hydroxylated benzyl
alcohols also reacted efficiently with indoline-2-thione without
requiring any additional protection/deprotection steps.
The BF3 etherate-catalyzed C-benzylation using benzyl alcohols
are known to proceed via a carbocation intermediate.25 The involve-
ment of benzyl carbocations appears most plausible in S-benzyla-
tion of indoline-2-thiones. The Lewis acid BF3 etherate upon
reaction with benzyl alcohol leads to the resonance-stabilized ben-
zyl carbocation intermediate. Subsequently, a nucleophilic attack of
the tautomeric thiol form of the indoline-2-thione (7) results in the
formation of the S-benzylated product. The profound effect of sub-
stitutions present on benzyl alcohols on the S-benzylation reaction
is in agreement with the mechanism proposed. The presence of
electron-donating groups such as –OMe, –OCH2O–, and –OH groups
stabilize the carbocation intermediate and the reaction is favored
with these benzyl group donors. The benzyl carbocation resulting
from benzyl alcohol is resonance-stabilized only with the aromatic
ring, and thus the reaction requires extra heating to go to comple-
tion. The 4-nitrobenzyl carbocation intermediate, on the other
hand, would be highly destabilized because of electron-withdraw-
ing nature of –NO2 group and is therefore not formed.
The mechanism proposed could also be used to explain the che-
moselectivity observed in the benzylation of indoline-2-thiones.
The indole-2-thione (7) 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 not only the most nucleophilic, but it
is also a soft nucleophile which will preferentially react with reso-
nance-stabilized benzyl carbocations which are soft electro-
philes.26 This results in exclusive formation of S-benzylated
products in the reaction. This observation is further substantiated
by one of our recent publications where a similar chemoselectivity
is reported in the acetylation of indoline-2-thione (7) using acetic
anhydride in the presence of a catalytic amount of 4-N,N-dimeth-
ylaminopyridine.27 For comparison, we treated indolin-2-one with
benzyl alcohol under similar conditions but the reaction did not
proceed; this highlights the unique nucleophilicity of S in indo-
line-2-thiones with respect to the O at C-2 in indolin-2-one.
Treatment of 1-methylindoline-2-thione (9) with 2 equiv of
benzyl alcohol under the reaction conditions described in Table 1
Acknowledgments
Financial support from Nipissing University (M.J.) and Ontario
Work Study Program Nipwork (O.E.) is gratefully acknowledged.
We would also like to thank Laurentian University and Acadia Uni-
versity for granting access to their analytical facilities.
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1.0 mmol), 4-methoxy benzyl alcohol (139 mg, 1.0 mmol) were dissolved in
dichloromethane and BF3 etherate (285 mg, 2.0 mmol) was added drop wise to
the solution. The reaction mixture was stirred at room temperature for 0.5 h.
The excess of dichloromethane was evaporated under reduced pressure and
the residue was subjected to FCC (silica gel, hexanes/ethyl acetate) to give 10
as a light yellow solid (238 mg, 88% yield). 1H NMR (300 MHz, CDCl3): d 7.82
(br s, 1H, D2O exchangeable), 7.57 (d, J = 8 Hz, 1H), 7.25–7.12 (m, 5H), 6.83 (d,
J = 8.5 Hz, 2H), 6.62 (s, 1H), 3.99 (s, 2H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3):
d 158.9, 137.0, 130.3, 129.9, 128.5, 128.4, 122.6, 120.3, 120.0, 114.0, 110.5,
109.4, 55.3, 41.4. FTIR mmax (KBr): 3348, 1448, 771 cmꢀ1. GC–MS (EI): m/z (%
relative abundance) 269 (M+, 8), 148 (6), 121(100).
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