Indium(III) chloride–catalyzed facile synthesis of oxabicyclo[3.3.1]nonenes via (3,5)-oxonium-ene cyclization

Article abstract of DOI:10.1080/00397911.2016.1196703

A practical and convenient method for the synthesis of oxabicyclo[3.3.1]nonenes has been developed using InCl₃(20?mol%) under mild conditions from aldehydes and R-(+)-limonene. Corresponding oxabicyclic compounds were obtained in high yields vi

Full text of DOI:10.1080/00397911.2016.1196703

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Indium(III)chloride Catalysed Facile Synthesis of
Oxabicyclo[3.3.1]nonenes via (3,5)-oxonium-Ene
Cyclization
Kulathooran Singaram & Dhamodaran Marimuthu
To cite this article: Kulathooran Singaram & Dhamodaran Marimuthu (2016):
Indium(III)chloride Catalysed Facile Synthesis of Oxabicyclo[3.3.1]nonenes via (3,5)-oxonium-
Ene Cyclization, Synthetic Communications
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1196703
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Date: 22 June 2016, At: 12:36

Indium(III)chloride Catalysed Facile Synthesis of Oxabicyclo[3.3.1]nonenes via
(3,5)-oxonium-Ene Cyclization
Kulathooran Singaram1, Dhamodaran Marimuthu2
1Research & Development Centre, Bharathiar University, Coimbatore, India
2Department of Chemistry, Perunthalaivar Kamarajar Institute of Engineering and
Technology, Karaikal, India.
Corresponding to author: Kulathooran Singaram, E-mail: chemkids@gmail.com.
Abstract
A practically convenient method for the synthesis of oxabicyclo[3.3.1]nonenes have been
developed using InCl3 (20 mol%) under mild conditions from aldehydes and R-(+)-
limonene. Corresponding oxabicyclic compounds were obtained in high yields via (3,5)-
oxonium-ene reaction. This protocol tolerates wide range of substituents and functional
groups. Mild reaction conditions, shorter time and convenient workup makes this
methodology more practical.
GRAPHICAL ABSTRACT
KEYWORDS: Limonene, Indium(III)chloride, Oxonium-Ene,
Oxabicyclo[3.3.1]nonenes
1

INTRODUCTION
Oxabicyclo[3.3.1]nonenes are one of the most stable oxygen containing heterocycles and
have been studied extensively for their unique biological properties such as estrogen
receptor ligands[1-4] and antileishmanial activity.[5] Compounds of this structural class
have been previously synthesised in acetic media of various clays.[6-9] Acidic clays and
resins hugely restricts the usage of acid sensitive functionalities and protecting groups,
especially for large scale reactions recovery procedure may require a more amount of
solvents. Pipas and co-workers have reported the synthesis of some oxabicyclo
compounds via (3,5)-oxonium-ene reaction of geraniol under lewis acidic conditions
(BF3.Et2O, 1.2 eq.) (Scheme 1).[10-11] Even though it is a unique method, the product
selectivity and yield are moderate especially due to polymerization of reactive geraniol
under super equimolar lewis acidic conditions. Similarly, Il’ina and co-workers have
reported the synthesis of oxabicyclo[3.3.1]non-7-en-6-one derivatives from verbenone
epoxide mediated by neutral montmorillonite clay (Scheme 2). The yield of the products
was very low due to the formation of side products.[12-13] Thus, a simple, general and
effective process for the synthesis of this important oxygen heterocyclic system is
required. We herein report a mild and high yielding methodology for the synthesis of
oxabicyclic compounds via (3,5)-oxonium-ene reaction[14-16] from R-(+)-limonene and
commercially available aldehydes (Scheme 3). This reaction is conveniently catalysed by
InCl3 (20 mol%) at ambient temperature.
2

RESULTS AND DISCUSSION
The optimization of the reaction conditions was endeavoured using R-(+)-limonene 1 and
benzaldehyde 2 as the model substrates (Table 1). Initially, the reaction was attempted
using Bronsted acid such as Glacial acetic acid and p-TSA.H2O, both at elevated
temperature and ambient temperature. However, we could not isolate any desired
product. Especially, at elevated temperature decomposition of Limonene was observed.
Further, we tried with varieties of lewis acids such as metal triflates including Yb(OTf)3,
Sc(OTf)3, metal chlorides such as InCl3, LaCl3 and strong Lewis acids such as BF3.Et2O
were screened to accomplish this transformation. We found metal triflates resulted
inferior results with full consumption of starting material. On the other hand, BF3.Et2O
resulted in trace product formation with complete decomposition of starting material (-78
oC and 0 oC). In the case of metal chlorides, InCl3 gave 30% of conversion at 0 oC. To our
delight, when the reaction was carried out at room temperature for 5h excellent yield was
obtained (80%). These results prompted further screening of the InCl3. Stirring at room
temperature for an extended period of time (12h), resulted similar yield. We also noticed
that at refluxing temperature reaction completed in 1h with 58% isolated yield. Instability
of the limonene under lewis acidic condition could be the reason for this diminishing
yield. To our delight, a gram scale reaction (1g) of Limonene and Benzaldehyde provided
the corresponding oxabicyclic product in comparable yield (77%) to that of milligram
scale. Product was further purified by column chromatography using 5% mixture of ethyl
acetate and hexane as eluent and characterized by NMR and mass spectrometry
techniques.
3

To prove the general applicability, different types of aromatic and aliphatic aldehydes
were subjected to react with Limonene and it was observed that, aliphatic and aromatic
aldehydes with different substitution (p-nitro, p-carbomethoxy, isophthalaldehye)
undergone reaction to give oxobicyclic products in moderate to good yields and shown in
Table 2.
We envisioned that treatment of R-(+)-limonene 1 with InCl3 would provide carbocation,
which could undergo subsequent nucleophilic attack by aldehyde 2 and result in oxonium
ion. The oxonium ion would be converted into oxabicyclic compound via (3,5)-oxonium-
ene cyclization reaction (Scheme 4).
EXPERIMENTAL
Material And Instruments
All the purchased reagents and solvents were of reagent grade and used without further
purification. Completion of reactions was monitored by TLC on silica gel-coated
aluminum sheets (Type 60 GF254). The melting points were measured in open capillaries
and are uncorrected. 1H and 13C NMR were recorded on a Bruker 400 MHz spectrometer
in CDCl3 as solvent. Mass spectrometric data were determined using an Agilent 1200
(Liquid chromatography) series instrument. Products were purified by flash column
chromatography using silica gel (60-120 mesh). The analytical and spectral data of the
synthesized compounds are given in the supplementary material to this paper.
4

General Procedure For The Synthesis Of Oxabicyclo[3.3.1]Nonenes 3(A-O)
To a solution of R-(+)-limonene (154 mg, 1.13 mmol) in DCM (2 mL) at 25 °C, was
added InCl3 (50 mg, 0.23 mmol) in one portion. To this solution, benzaldehyde (120 mg,
1.13 mmol) in DCM (2 mL) was added dropwise over 10 minutes. The reaction mixture
was stirred at room temperature for 5 hr. The progress of the reaction was monitored by
TLC with 5% ethyl acetate and hexane as eluent. After completion of the reaction, the
solvent was removed by rotary evaporator. The resultant residue was quenched with
saturated NaHCO3 solution. The product was extracted with ethyl acetate (2 X 10 mL)
and washed with brine (10 mL). The organic layer was dried (Na2SO4) and evaporated to
leave the crude product, which was further purified by short column chromatography
over silica gel to obtain 2,2,6-Trimethyl-4-phenyl-3-oxabicyclo[3.3.1]non-6-ene (3a) as a
colourless oil. The above general method was adopted for the synthesis of compounds
3(b-o) of this series.
CONCLUSION
In conclusion, we demonstrated an facile, economic, room temperature approach for the
synthesis of oxabicyclo[3.3.1]nonenes from readily available starting material. This
protocol tolerates variety of functional and protecting groups. This method works well
even in gram scale synthesis without any specific safety requirements thus may find
application in industrial perspective.
5

FUNDING
We gratefully acknowledge financial support of this work by Hi-Tech Project Industries,
Nagapattinum-611001, India.
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6

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7

Table 1. Optimization of reaction conditions.a
Entry
1
Catalyst
mol (%)
Temp. (°C) 3b (%)
Glacial acetic acid 20
Glacial acetic acid 20
r.t.(12h)
reflux(1h)
r.t.(12h)
reflux(1h)
r.t.(12h)
r.t.(12h)
r.t.(12h)
-78(2h)
0(2h)
_
2c,d
3
_
p-TSA.H2O
p-TSA.H2O
Yb(OTf)3
Sc(OTf)3
LaCl3
20
20
20
20
20
100
20
20
20
20
20
_
4c
_
5c
27
56
22
18
26
30
58
80
78
6c
7
8c
BF3.Et2O
BF3.Et2O
InCl3
9c
10
11c
12
13
0(5h)
InCl3
reflux(1h)
r.t.(5h)
InCl3
InCl3
r.t.(12h)
a Reaction conditions: 1 (1.13 mmol), 2 (1.13 mmol), cat. (20 mol%, except entry 8),
solvent (4 mL) for 5 h.
bIsolated yield.
cStarting material fully consumed.
dTHF was used as solvent
8

Table 2. Reaction of R-(+)-limonene with aldehydes.
Entry
R-CHO
C6H5-CHO
Time (h)
Yielda
80
3a
5
5
4
5
5
5
5
5
5
5
4
4
4
5
5
3b
CH3CH2CH2-CHO
p-NO2-C6H4-CHO
C10H7-CHO (1-Naphthyl)
p-(CH3)2CH-C6H4-CHO
C10H5-(CH2)2-CHO
1-CHO-C6H4-3-CHO
p-CH3O2C-C6H4-CHO
p-CH3O-C6H4-CHO
p-Cl-C6H4-CHO
62
3c
69
3d
74
3e
76
3f
67
3g
58
3h
60
3i
69
3j
74
3k
p-Br-C6H4-CHO
56
3l
p-F-C6H4-CHO
68
3m
2-NO2-C6H4-CHO
CH3CH2-CHO
74
3n
59
3o
p-CH3-C6H4-CHO
77
aIsolated yields.
The compounds are characterized by 1H, 13C and mass spectroscopy.
Entry 3a to 3o are repeated compounds except entries 3e-3g.
9

Scheme 1. Pipas’s work
10

Scheme 2. Il’ina’s work
11

Scheme 3. Present work
12

Scheme 4. Proposal for the formation of oxabicyclic compounds.
13