Indium trifluoromethanesulfonate (In(OTf)3). A novel reusable catalyst for intramolecular Diels-Alder reactions

Article abstract of DOI:10.1016/S0040-4039(00)01513-6

Indium trifluoromethanesulfonate (In(OTf)₃) is found to be an effective catalyst for intramolecular Diels-Alder reactions of furans. This novel catalyst, soluble in both aqueous and organic media, is easily recovered from the aqueous layer afte

Full text of DOI:10.1016/S0040-4039(00)01513-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8639–8643
Indium trifluoromethanesulfonate (In(OTf)3). A novel
reusable catalyst for intramolecular Diels–Alder reactions
Dipak Prajapati,* Dhrubojyoti D. Laskar and Jagir S. Sandhu
Regional Research Laboratory, Jorhat-785 006, Assam, India
Received 5 June 2000; revised 30 August 2000; accepted 7 September 2000
Abstract
Indium trifluoromethanesulfonate (In(OTf)3) is found to be an effective catalyst for intramolecular
Diels–Alder reactions of furans. This novel catalyst, soluble in both aqueous and organic media, is easily
recovered from the aqueous layer after the reaction is completed. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: indium triflate; intramolecular Diels–Alder reactions; epoxyisoindolines; furfuryl-N-arylamines.
In recent years organic chemistry has witnessed the increased use of indium reagents.1 It was
found that the low reactivity of trivalent organoindium reagents can be increased by complex
formation with organolithium compounds.2 The tetra-organo-indates thus prepared are suffi-
ciently reactive to take part in reactions at ambient temperature.2a Allylic indates react with
imides and nitriles regioselectively at the g-carbon to give homoallylamines.2b Also indium
metal3 has been found to be an effective reducing agent and indium(III) halide complexes act4a
as efficient Lewis acid catalysts in Mukaiyama aldol reactions, Friedel–Crafts acylations,3
Diels–Alder reactions4b in water and hetero Diels–Alder cycloadditions.4c Our interest in
catalytic carbonꢀcarbon bond formation5 prompted us to investigate the use of indium in
Scheme 1.
* Corresponding author. Fax: +91 0376 370011; e-mail: drugs@csir.res.in
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01513-6

8640
cycloaddition reactions (Scheme 1 and Table 1). In recent years indium triflates have received
increasing attention both as reagents and catalysts for organic reactions.6 These triflates have
been shown to be effective, water tolerant, Lewis acids in several carbonꢀcarbon bond forming
reactions and in some cases the presence of water even improves their activity. Herein, we report
a novel catalyst, indium triflate, for intramolecular Diels–Alder reactions of furans.
Table 1
Reuse of the catalyst
Entry
Run
Product
Yield (%)
1
2
3
1st
2nd
3rd
4a
4a
4a
85
83
80
The (2-furfuryl)aniline7 1 (R=H, Ar=Ph) was mixed with allyl bromide and a catalytic
amount of indium trifluoromethanesulfonate in an Erlenmeyer flask and irradiated using
microwaves for 8 min (Table 2). After the usual work-up, the corresponding IMDA product 4a
was obtained in 85% yield, mp 120–121°C, along with the acyclic product 3a as a light yellow
oil in 10% yield. The diagnostic signal for the furan proton H-1, which was present at l 7.10 in
1
the H NMR spectrum of 1, was absent in the spectrum of the cycloadduct, whilst the upfield
shift of this proton to l 5.07 showed that cycloaddition had occurred to the furan ring. It is
worth mentioning here that this type of IMDA reaction has been reported earlier by Bilovic et
al.8 in which (2-furfuryl)aniline was allowed to react with allyl iodide and the resulting
crystalline hydroiodide salt was treated with sodium hydroxide to give oily allyl(2-fur-
furyl)aniline 3a in 51% yield. On standing for several days, the oily amine 3a began to crystallize
and was transformed into the corresponding epoxyisoindoline 4a. Also, it is reported that the
IMDA product 4 can undergo retro Diels–Alder reaction on distillation. In contrast to this
report, indium triflate completes the reaction within 8–10 min giving excellent yields of the
IMDA product in solvent-free conditions.9 The reaction is less effective when carried out under
thermal conditions and takes about 25–30 min giving 40–45% yields. To check the role of HBr
formed, a control experiment was performed without using In(OTf)3 under microwave activa-
tion. It was observed that when irradiated for 20 min, a mixture of linear 3a (20%) and IMDA
4a (6–8%) products was formed. Increasing the reaction time further had no significant effect on
the yield and resulted in decomposition, which rules out the participation of the HBr formed in
the course of the reaction as catalyst. Moreover, the formation of HBr salt was not detected,
probably due to the fact that the excess of allyl bromide removed the HBr from the mixture.
When prenyl bromide was used in place of allyl bromide and the mixture irradiated for 20 min
no IMDA products were obtained. However, the corresponding linear products were obtained
in 25% yield. Interestingly, when thiophene analogues of 1 were used, only N-allylation could be
observed and no IMDA products were formed.
To include an example of a tricyclic epoxyisoindoline, we have carried out the reaction of
furfuryl-N-p-toluidine with cyclohexenyl bromide in the presence of a catalytic amount of
indium triflate under microwave irradiation in the solid state.10 Here, the reaction proceeds
similarly and affords a mixture of acyclic and cyclic products in 20 and 22% yields, respectively,
when irradiated for 8 min (Scheme 2). The epoxyisoindoline thus obtained, upon attempted
recrystallization in benzene at 80°C, suffers a retro Diels–Alder reaction. To improve the yield,

Table 2
In(OTf)3 catalyzed intramolecular Diels–Alder reaction under microwave activation
Entry Compound
no.
Ar
R
Reaction time, min
microwave
Reaction time,
min thermal
Mp (°C)
Yield (%)
thermal 4
Yielda (%)
microwave 4
Yieldb (%)
microwave 3
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
C6H4Cl-p
C6H4Cl-m
H
H
H
H
H
H
H
H
H
8
9
8
10
9
8
8
9
10
25
30
30
28
25
30
25
30
25
30
25
120–121
118–120
83–84
40
45
40
40
45
45
40
42
45
40
45
85
80
82
85
90
80
80
82
82
80
80
10
10
8
C6H4OC2H5-p
C6H4OCH3-p
C6H4CH3-p
C6H4Br-p
C6H4OCH3-m
C6H4CH3-m
C6H4CH3-p
C6H4CH3-p
97–99
10
10
12
10
10
12
10
10
138–139
108–110
129–130
125–126
121–122
162–163
149–150
10
11
4j
4k
NO2 10
Cl
8
a All the yields refer to isolated chromatographically pure compounds.
b Epoxyisoindolines identified by spectral comparison with independently prepared authentic samples.

8642
the acyclic product was first prepared by reacting furfuryl-N-p-toluidine with cyclohexenyl
bromide in the presence of potassium carbonate and TBAB. It was separated and then cyclized
under microwave irradiation in the presence of In(OTf)3. After 20 min of irradiation it gave only
15% of the IMDA products and further increasing of reaction time affords only the decompo-
sition products. The advantage of In(OTf)3 as a Lewis acid catalyst is that it can be easily
recovered and reused. After the reaction is completed and the IMDA adduct is extracted with
dichloromethane, the aqueous layer is concentrated to remove the water under reduced pressure.
In(OTf)3 is almost quantitatively recovered and the recovered catalyst is also effective in the
IMDA reaction. It should be noted that the yield of second and even third runs are comparable
to that of first run.
Scheme 2.
Therefore, this new method using indium triflate under microwave activation has the
following advantages: (a) The reaction is complete in a few minutes affording high yields of
IMDA products; (b) Instead of isolating salts the reaction proceeds in one-step; and (c) The
catalyst can be recovered and reused. We believe this reaction offers considerable synthetic
potential because of the two following reasons. Firstly, transformation of the furan to an indole
derivative by cleavage of epoxy bridge of the adduct and concomitant aromatization and,
secondly, the availability of a large number of functionalized furans. Further investigations to
develop synthetic techniques, especially carbonꢀcarbon bond forming reactions using this novel
reusable catalyst are now in progress.
Acknowledgements
We thank the Department of Science and Technology (DST), New Delhi, for the financial
assistance. One of us (D.D.L.) thanks the Council of Scientific Industrial Research (CSIR), New
Delhi, for the award of a senior research fellowship.
References
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8643
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(60 mg, 0.1 mmol) were mixed together without solvent in an Erlenmeyer flask and placed in a commercial
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(monitored by TLC) and after completion it was allowed to cool to room temperature, washed with water and
extracted with CH2Cl2 (2×30 ml) and dried over anhydrous sodium sulfate. Removal of solvent and the residue
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ing IMDA product N-phenyl-4H-5,7a-epoxyisoindoline 4a, mp 120–21°C, in 85% yield (entry 1) along with the
acyclic product allyl(2-furfuryl)aniline 3a (light yellow oil) in 10% yield. Similar treatment of other furfuryl-N-
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[N-(phenyl)-5,7a-epoxy-4H-isoindoline (Ar=Ph R=H)]. IR (KBr, cm−1): 2995, 2825, 1650, 1575. MS m/z: 213
1
(M+). H NMR (300 MHz, CDCl3): l 1.46 (dd, J=7.6 and 11.6 Hz, 1H, 4-H), 1.84 (m, 1H, 3a-H), 2.18 (m, 1H,
4-H), 2.93 (t, J=9 Hz, 1H, 3-H), 3.00 (d, J=11.4 Hz, 1H, 1-H), 3.75 (t, J=9 Hz, 1H, 3-H), 3.91 (d, J=11.4 Hz,
1H, 1-H), 5.07 (dd, J=1.6 and 4.4 Hz, 1H, 5-H), 6.39–6.70 (m, 5H, ArH), 7.18 (m, 1H, 6-H), 7.24 (d, J=2 Hz,
1H, 7-H). Anal. calcd for C14H15NO: C, 78.87; H, 7.04; N, 6.57. Found: C, 78.61; H, 6.90; N, 6.65. Similarly,
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