Enantioselective cycloetherification in a micellar catalysis system

Article abstract of DOI:10.1016/S1872-2067(10)60169-6

The enantioselective cycloetherification of substituted keto phenols into their corresponding dihydrobenzofuran derivatives was carried out using hydrogen peroxide and chiral quaternary ammonium iodide in micellar media. This approach increased the conversion rate of cycloetherification and also widened the scope of this particular reaction for various substituted keto phenols with electron withdrawing as well as electron donating functionalities. The use of a surfactant in the cycloetherification reaction increased the yield of the corresponding enantioselective dihydrobenzofuran four times. The conversion rate of keto phenols into their corresponding dihydrobenzofuran derivatives was proportional to the concentration of the surfactant used in the reaction.

Full text of DOI:10.1016/S1872-2067(10)60169-6

CHINESE JOURNAL OF CATALYSIS
Volume 32, Issue 2, 2011
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2011, 32: 231–234.
SHORT COMMUNICATION
Enantioselective Cycloetherification in a Micellar Catalysis
System
Bhupesh S. SAMANT1,*, Sunil S. BHAGWAT2
1Natural Product and Medicinal Chemistry Research Group, Division of Pharmaceutical chemistry, Faculty of Pharmacy, Rhodes
University, Grahamstown, 6140, South Africa
2Department of Chemical Engineering, Institute of Chemical Technology, Matunga, Mumbai, 400 019, India
Abstract: The enantioselective cycloetherification of substituted keto phenols into their corresponding dihydrobenzofuran derivatives was
carried out using hydrogen peroxide and chiral quaternary ammonium iodide in micellar media. This approach increased the conversion rate
of cycloetherification and also widened the scope of this particular reaction for various substituted keto phenols with electron withdrawing
as well as electron donating functionalities. The use of a surfactant in the cycloetherification reaction increased the yield of the corre-
sponding enantioselective dihydrobenzofuran four times. The conversion rate of keto phenols into their corresponding dihydrobenzofuran
derivatives was proportional to the concentration of the surfactant used in the reaction.
Key words: enantioselective cycloetherification; dihydrobenzofuran derivative; micellar catalysis
Chiral 2-substituted-2,3-hydrobenzofuran is the backbone
structure for many biologically active compounds in medicinal
chemistry [1–8]. As part of our ongoing research [9,10] into
novel chemical entities with antitrypanosomal activities we
became interested in the synthesis of (+)-remirol and
(+)-remiridiol (1) from (R)-(4,6-dimethoxy-2,3- dihydroben-
zofuran-2-yl) (phenyl methanone, 2) (Scheme 1).
nium iodide [19]. Recently, a very useful synthesis of
2-substituted-2,3-hydrobenzofuran using N-spiro quaternary
ammonium iodide has been reported [20]. In this report the
cyclization was catalyzed by in situ-generated chiral quater-
nary ammonium (hypo)iodite salts with hydrogen peroxide as
an environmentally benign oxidant. This process successfully
avoids the use of rare and/or toxic metals as catalysts for the
oxidative reactions of inorganic iodine derived oxoacids and,
therefore, replace aryliodane or transition metal catalysts.
However, this method requires a long reaction time for an
improved yield. Limitations in the synthesis of dihydroben-
zofuran derivatives and their important applications in various
fields have led to an increase in research about new method-
ologies of cycloetherification for the later stages of total syn-
thesis and with substrates containing heavy functionalities. A
unique approach to overcome these limitations is the use of
micelles in the reaction medium.
Although a number of methods for the synthesis of
2-substituted-2,3-hydrobenzofuran have been reported [11–18]
they generally require very harsh conditions and most result in
racemic mixtures of the product. One of the most important
approaches in the synthesis of chiral 2-substituted-2,3- hy-
drobenzofuran is the use of hydrogen peroxide as an oxidant to
activate the catalytic ion pairs of the chiral quaternary ammo-
X
H CO
3
O
H CO
3
O
COPh
Ac
Micelles are self-assembled nanostructures of amphiphilic
monomers that form a hydrophilic outer shell area and a hy-
drophobic core. The use of micelles as a reaction medium is
widespread and has been investigated in detail for different
reactions in aqueous and organic solvents [21–24]. Most aro-
OCH
3
OCH
3
Remirol X = H
Remiridiol X = OH
2
1
Scheme 1. Retrosynthetic approach for remirol and remiridiol.
Received 22 November 2010. Accepted 22 December 2010.
*Corresponding author. Tel: +27-46-6038395, Fax: +27-46-6361205; E-mail: B.Samant@ru.ac.za
Foundation item: Supported by the Rhodes University Joint Research Committee (JRC, grant number 35047).
Copyright © 2011, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(10)60169-6

Bhupesh S. SAMANT et al. / Chinese Journal of Catalysis, 2011, 32: 231–234
O
O
OH
PhLi, THF
R1
R1
ꢀ78 oC to rt
COPh
Scheme 2. Synthesis of 3-13.
N
I
matic compounds have very low solubility in water and the
presence of water adversely affects the product yield. There-
fore, organic solvents (non polar media) are often used for
various organic reactions. The cost effective and eco-friendly
option of using micellar aggregates as microreactors enhances
the scope of organic reactions. Previously, we reported on an
improvement in the regioselectivity of aromatic chlorination
[21] and the nitration of aromatic aldehydes [9,10] by the use of
micelles. In continuation of this work we now propose a novel
improvement in the enantioselective cycloetherification of
substituted keto phenols into the corresponding dihydroben-
zofuran derivatives.
Scheme 3. The chiral R,R-quaternary ammonium iodide used in the
enantioselective cycloetherification of 3.
ane-EtOAc = 4:1 to give product 2 as a white solid; yield: 281
mg (99% yield, racemic mixture, Table 1, entry 1). Three in-
dependent tests were done and the variation in results was r
0.75%. When we replaced THF with diethyl ether (Et2O)/H2O
and Bu4N+I– with chiral quaternary ammonium iodide
(R,R-R4N+I–, Scheme 3) the yield of the reaction decreased
with an increase in enantioselectivity (Table 1, entry 2). The
synthesis and characterization of the R,R-quaternary ammo-
nium iodide (R4N+I–) was done as described elsewhere [20]. By
replacing THF/Et2O with toluene/H2O the yield of the
cycloetherification reaction was moderate with very poor en-
antioselectivity (Table 1, entry 3). On the other hand, when the
reaction was carried out in the micellar media by adding so-
dium dodecylsulphate (SDS) surfactant an increase was ob-
served in the enantioselectivity as well as in the yield of the
reaction (Table 1, entry 4). For this reaction we added 30 wt%
hydrogen peroxide (0.0021 ml, 2.0 mmol) to an agitated mix-
ture of 3 (286 mg, 1 mmol, 1 equiv) as well as chiral
The synthesis of 3-[2(3,5-dimethoxyphenol)-1-phenyl-
propane-1-one (3, Scheme 2) was carried out as described
earlier [25]. To an agitated mixture of 5,7-dimethoxy chro-
man-2-one (208 mg, 1 mmol) in THF-Et2O (1:5 (v/v), 5 ml),
PhLi (0.92 ml, 1.1 mol/L, 1.0 mmol) was added slowly at –78
°C. After 7 h, the resulting mixture was poured into aqueous
NH4Cl (5 ml), extracted with EtOAc (2 × 5 ml), and washed
with brine. The combined organic layers were dried over an-
hydrous Na2SO4 and the solvents were removed in vacuo. The
residue was purified by flash column chromatography on silica
gel (hexane/EtOAc) to afford 223 mg of 3 in 78% yield.
For the cycloetherification reaction, in an agitated mixture of
3 (286 mg, 1 mmol, 1 equiv), Bu4N+I– (36.9 mg, 0.10 mmol, 10
mol%), tetrahydrofuran (THF, 5 cm3), and 30 wt% hydrogen
peroxide (0.0021 ml, 2.0 mmol) were added. The mixture was
agitated for 1 h in a 50 cm3 baffled glass reactor equipped with
a six-blade turbine agitator of 0.3 cm diameter. The speed of
agitation was maintained at 1.67 Hz. Isothermal conditions
were maintained at 25 °C. After 5 h, the resulting mixture was
poured into water (20 ml) and the aqueous phase was extracted
twice with EtOAc. The combined organic layers were washed
with a saturated Na2SO3 solution, brine, and water. The com-
bined organic layers were dried over anhydrous Na2SO4 and
the solvents were removed in vacuo. The crude product was
purified by flash chromatography on silica gel using hex-
R,R-R4N+I– (11.38 mg, 0.01 mmol) in
a SDS (60
mmol)-toluene (10 cm3) solution. The mixture was agitated for
1 h in the baffled glass reactor. The speed of agitation was
maintained at 1.67 Hz. Isothermal conditions were maintained
at 25 °C. A cetyltrimethyl ammonium bromide (CTAB, 60
mmol) and toluene (5 cm3) solution was added to the reaction
mixture and agitated for an extra 2 min. The mixture was fil-
tered through a plug of celite. The filtrate was concentrated
under reduced pressure and purified by flash chromatography
on silica gel using hexane/EtOAc = 4:1 to give the product 2 as
a white solid; yield: 281 mg (99% yield, 90% ee).
All the products formed were solubilized in CDCl3 and
Table 1 Cycloetherification of 3
H3CO
O
H3CO
OH
H2O2 (30%, 2 equiv)
rt
COPh
COPh
OCH3
OCH3
Entry
Reagent and condition
Reaction time (h)
Yield (%)
ee (%)
1
2
3
4
THF, Bu4N+Iꢀ (10 mol%)
Et2O + H2O (5:1, v/v), R,R-R4N+Iꢀ (10 mol%)
Toluene + H2O (5:1, v/v), R,R-R4N+Iꢀ (10 mol%)
5
24
24
1
99
25
50
99
Racemic mix.
69
2
Toluene + H2O (5:1, v/v), R,R-R4N+Iꢀ (10 mol%), SDS (60 mmol)
90
ee—enantiomeric excess.

Bhupesh S. SAMANT et al. / Chinese Journal of Catalysis, 2011, 32: 231–234
identified satisfactorily using H NMR (300 MHz) and 13C
NMR (75.46 MHz). The peak positions are given in parts per
million (į) using tetramethylsilane as an internal standard, and
the coupling constant values (J) are given in Hz. Reagent
conversion was analyzed using a gas chromatograph (Chemito
8610) with a flame ionization detector. A 4 m long and 0.37 cm
internal diameter stainless steel column packed with 10%
SE-30 on chromosorb WHP was employed for the analysis. N2
at a flow rate of 0.5 u 10ꢀ7 m3/s was used as the carrier gas. The
ee of all the products was determined by high-performance
liquid chromatography (HPLC) using hexane-iPrOH as the
mobile phase and a 25 cm long, 4.6 mm internal diameter chiral
column of Daicel CHIRALCEL OD-H.
ena.
The applicability of this enantioselective cycloetherification
1
reaction in the micellar medium to obtain various substituted
2,3-hydrobenzofurans is shown in Table 2 wherein keto phenol
derivatives that have electron withdrawing as well as electron
donating functionalities were converted into their corre-
sponding dihydrobenzofuran derivatives with excellent yield
and high enantioselectivity. These results demonstrate the
scope of the micellar catalyzed enantioselective cycloetherifi-
cation in the total synthesis of various pharmaceutically im-
portant, biologically active compounds.
To study the exact reaction mechanism of the enantioselec-
tive cycloetherification, several experiments were optimized to
identify the role of micellar media in the activation of the
hypervalent iodine species. [R4N]+[IO]– is generated as an
active oxidant species in the reaction between I2 and tetrasub-
stituted ammonium hydroxide (R4N+OH–) [26]. The anisot-
ropic interface of the micellar aggregate (located between the
outer hydrophilic bulk and the inner organic core) acts as a
useful site for the activation of the hypervalent iodine species.
Hydrophilic hydrogen peroxide oxidizes the relatively hydro-
phobic R4N+I– at the anisotropic interface of the micellar ag-
gregates to generate [R4N]+[IO] –. This active oxidant species
further reacts with a corresponding substrate to give dihydro-
benzofuran derivatives with high yield and excellent enanti-
oselectivity.
Figure 1 shows the effect of concentration and the nature of
the surfactant on the yield of product 2 in the reaction. The
conversion of 2 increased with an increase in the surfactant
concentration and remained constant beyond a specific sur-
factant concentration (60 mmol for SDS). Two types of ionic
surfactants i.e. anionic (SDS and LABS), and cationic (CTAB)
were used to study the effect of micellar head group charges on
the rate and selectivity of the reaction. However, no difference
was observed in the rate or the yield of the reaction product for
these ionic surfactants indicating that the hydrophobic and
hydrophilic media are the driving factors rather than the nature
of the charges on the micellar head and tail groups.
The conversion (approximately 10%–15%) remained rela-
tively unchanged at surfactant concentrations up to 30–35
mmol. This might be because of an insufficient number of
micelles present in the reaction mixture. We observed that once
the concentration of the surfactant exceeds the critical micellar
concentration and reaches a specific concentration (25 mmol
for SDS) an increase occurs in the reaction rate. This concen-
tration is known as the effective micellar concentration and a
sufficient number of micelles were present in the reaction
medium to affect the reaction rate. This indicates that an in-
crease in the conversion rate of the enantioselective
cycloetherification reaction was caused by micellar phenom-
In conclusion, the cycloetherification of substituted keto
phenols to their corresponding dihydrobenzofuran derivatives
was improved using a micellar reaction medium. The anisot-
ropic palisade layer of the ionic micelles acts as an effective
reaction site for the generation of the active oxidant species
[R4N]+[IO]–. A high yield of the enantioselective dihydroben-
zofuran derivative as a product was obtained using this ap-
proach. The overall scope of this cycloetherification pathway
was widened to include various substrates especially in the
Table
2
Applicability of micellar catalyzed enantioselective
cycloetherification for various substrates
ꢀ
+
R N I ꢁ(10 mol%),
4
100
OH
O
H O (30 wt%, 2 equiv)
2
2
1
1
COPh
R
R
SDS (60 mmol),
COPh
80
toluene + H O (5:1 v/v),
2
rt
Reaction
60
Substrate
Yield (%) ee (%)
time (h)
4, R1 = H
1
99
99
99
99
99
99
99
99
99
99
91
90
88
92
94
89
88
85
89
87
40
5, R1 = 5-OMe
6, R1 = 5-OEt
7, R1 = 5-F
8, R1 = 5-Cl
9, R1 = 5-Br
1
SDS
LABS
CTAB
1
20
0
1
1
1
0
10 20 30 40 50 60 70 80 90
Surfactant concentration (mmol)
10, R1 = 4-Me, 6-Me
1.5
2
11, R1 = 3-Me, 4-Me, 5-Me, 6-Me
12, R1 = 2-OMe, 3-Ac, 4-OMe
13, R1 = 2-OMe, 3-Ac, 4-OMe, 5-OMe
Fig. 1. The effect of surfactant concentration on the cycloetherification
of 3 in the presence of 10 mol% Bu4N+Iꢀ, 2 equiv H2O2 (30 wt%) and
toluene + H2O (5:1 v/v) at 25 °C for 1 h.
1.5
2

Bhupesh S. SAMANT et al. / Chinese Journal of Catalysis, 2011, 32: 231–234
6
7
8
9
Céspedes C L, Uchoa A, Salazar J R, Perich F, Pardo F. J Agric
total synthesis of biologically active compounds. The use of
micellar microreactors in the cycloetherification reaction in-
creased the yield of the corresponding dihydrobenzofuran
derivatives four times with a reduction in the reaction time
from 1 to 24 h. The conversion of keto phenols to their corre-
sponding dihydrobenzofuran derivatives was directly propor-
tional to the concentration of the surfactant used in the reaction.
Ionic surfactants (anionic and cationic) with a concentration of
60 mmol and above gave a 99% yield for the reaction. We
observed that the effect of hydrophobic and hydrophilic media
has more influence in increasing the yield than the nature of the
charges on the micellar head and tail groups. The presented
data shows the applicability of micellar media in increasing the
rate of a reaction for a particular product and this method can
be efficiently employed for various other reactions.
Food Chem, 2002, 50: 2283
Banskota A H, Tezuka Y, Prasain J K, Matsushige K, Saiki I,
Kadota S. J Nat Prod, 1998, 61: 896
Bowen D M, Shah V R, DeGraw J I Jr, Bonner W A. J Med
Chem, 1963, 6: 315
Samant B S, Sukhthankar M G. Med Chem, 2009, 5: 293
10 Samant B S, Sukhthankar M G. Bioorg Med Chem Lett, DOI:
10.1016/j.bmcl.2010.12.040
11 Kawase Y, Yamaguchi S, Kondo S, Shimokawa K. Chem Lett,
1978, 7: 253
12 Yamaguchi S, Kondo S, Shimokawa K, Inoue O, Sannomiya
M, Kawase Y. Bull Chem Soc Jpn, 1982, 55: 2500
13 Yamaguchi S, Miyata A, Ueno M, Hase T, Yamamoto K, Ka-
wase Y. Bull Chem Soc Jpn, 1984, 57: 617
14 Yamaguchi S, Sugiura K, Fukuoka R, Okazaki K, Takeuchi M,
Kawase Y. Bull Chem Soc Jpn, 1984, 57: 3607
15 Yamaguchi S, Saito A, Kawase Y. Bull Chem Soc Jpn, 1986,
59: 3983
Supplementary data
16 Yamaguchi S, Takai M, Hanazome I, Okada Y, Kawase Y. Bull
Chem Soc Jpn, 1987, 60 : 3603
Supplementary data include the synthesis process, the CMC
determination and characterization data (1H NMR, 13C NMR,
elemental analysis and isolated yield) for compounds 3–13 and
all the products.
17 Yamaguchi S, Miyakawa R, Yonezawa S, Kawase Y. Bull
Chem Soc Jpn, 1989, 62: 3593
18 Yamaguchi S, Nitta T, Hosaka T, Nishino Y, Kawase Y. Bull
Chem Soc Jpn, 1990, 63: 3230.
References
19 Matsuzaki I, Nakajima T, Liebhafsky H A. Chem Lett, 1974, 3:
1463
1
2
3
4
Duan J A, Wang L Y, Qian S H, Su S L, Tang Y P. Arch
Pharmcal Res, 2008, 31: 965
20 Uyanik M, Okamoto H, Yasui T, Ishihara K. Science, 2010,
328: 1376
Ito C, Itoigawa M, Kumagaya M, Okamoto Y, Ueda K, Nishi-
hara T, Kojima N, Furukawa H. J Nat Prod, 2006, 69: 138
Cohen J L, Limon A, Miledi R, Chamberlin A R. Bioorg Med
Chem Lett, 2006, 16: 2189
21 Samant B S, Saraf Y P, Bhagwat S S. J Colloid Interface Sci,
2006, 302: 207
22 Dwars T, Paetzold E, Oehme G. Angew Chem Int Ed Engl,
2005, 44: 7174
Chu G H, Gu M H, Cassel J A, Belanger S, Graczyk T M,
DeHaven R N, Conway-James N, Koblish M, Little P J,
DeHaven-Hudkins D L, Dolle R E. Bioorg Med Chem Lett,
2005, 15: 5114
23 Wang F, Liu H, Cun L F, Zhu J, Deng J G, Jiang Y Z. J Org
Chem, 2005, 70: 9424
24 Witula T, Holmberg K. Langmuir, 2005, 21: 3782
25 Li K L, Vanka K, Thompson W H, Tunge J A. Org Lett, 2006,
8: 4711
5
Shi G Q, Dropinski J F, Zhang Y, Santini C, Sahoo S P, Berger
J P, MacNaul K L, Zhou G C, Agrawal A, Alvaro R, Cai T Q,
Hernandez M, Wright S D, Moller D E, Heck J V, Meinke P T.
J Med Chem, 2005, 48: 5589
26 Yamada S, Morizono D, Yamamoto K. Tetrahedron Lett, 1992,
33: 4329