Friedel-Crafts alkylation of arenes with epoxides promoted by fluorinated alcohols or water

Article abstract of DOI:10.1039/b926684d

The stereoselective intra- and intermolecular Friedel-Crafts alkylation of electron-rich arenes with epoxides can take place in refluxing 1,1,1,3,3,3-hexafluoroisopropanol owing to its weak acidity and high ionizing power.

Full text of DOI:10.1039/b926684d

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Friedel–Crafts alkylation of arenes with epoxides promoted
by fluorinated alcohols or waterw
Guo-Xing Li and Jin Qu*
Received (in College Park, MD, USA) 17th December 2009, Accepted 9th February 2010
First published as an Advance Article on the web 10th March 2010
DOI: 10.1039/b926684d
The stereoselective intra- and intermolecular Friedel–Crafts
alkylation of electron-rich arenes with epoxides can take place
in refluxing 1,1,1,3,3,3-hexafluoroisopropanol owing to its weak
acidity and high ionizing power.
Table 1 Intramolecular cyclialkylation of epoxide 1aa
The regio- and stereoselective Friedel–Crafts alkylation of
arenes with epoxides is important in organic synthesis. These
reactions are regularly catalyzed by Lewis acids which activate
epoxides towards electrophilic substitution.1 However,
sometimes degradation and polymerization of epoxides occur
before electrophilic substitution in the presence of strong
Lewis acids. In 2004, He’s research group reported that
AuCl3/3AgOTf could catalyze the cyclialkylation of arenes
with tethered epoxides in moderate to good yields.2 Recently,
Pericas’s research group reported that the cyclialkylation of
arenes with tethered epoxides could be efficiently catalyzed by
common Lewis acids such as BF3ÁEt2O or FeBr3 with the
reaction catalyzed by FeBr3/3AgOTf giving the highest yield.3
We recently reported that water (60–100 1C) could promote
the ring-opening of epoxides and aziridines with heteroatom
nucleophiles. Mechanistic studies showed that water acted as a
mild acid catalyst at elevated temperature.4 This stimulated us
to check if water can replace Lewis acids in more important
carbon–carbon bond formation reactions. Herein we report
that the intra- and intermolecular Friedel–Crafts alkylation of
electron-rich arenes with epoxides can take place in water and
fluorinated alcohols without additional catalyst.
Yield
Time (%)b
Entry Solvent
Condition
1
2
3
4
5
6
7
8
9
Toluene
Acetone
CH3CN
MeOH
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
26 h N.R.
26 h N.R.
26 h N.R.
26 h 18
10 h 55c
48 h 96
TFE
HFIP
TFE
HFIP
r.t.
4 h
99
Reflux (74 1C) 4.5 h 99
Reflux (59 1C) 5 min 99
10d Phenol (20 mol%) in H2O
Reflux
19 h 77c
3.5 h 41c
40 min 12c
11d 4-Nitrophenol (20 mol%) in H2O Reflux
12d AcOH (20 mol%) in H2O
Reflux
a
The reaction was conducted with 0.15 mmol of 1a in 5 mL of the
c
indicated solvent. Isolated yield. The conversion of 1a was 100%
b
and the only by-product was diol from the hydrolysis of epoxide.
d
The amount of additive is the mole percent relative to the amount of
substrate.
Fluorinated alcohols are known for their acidic properties
and can promote the ring-opening of epoxides with aromatic
amines.6 Treatment of 1a in 2,2,2-trifluoroethanol (TFE) at
room temperature for 48 h provided 2a in 96% yield. Replacing
TFE with more acidic 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) shortened the reaction time to 4h. When the reaction
was carried out in refluxing HFIP, the cyclialkylation finished
within 5 min and gave quantitative yield of 2a. The reaction is
regio- and stereocontrolled because only endo cyclization with
an SN2-like inversion of the chiral center is observed and the
isolated product is enantiomerically pure (499% ee). Phenol
is more acidic and less nucleophilic than water and was
reported to catalyze the epoxide-opening with amines.7 By
using water containing 0.2 equiv. of phenol as reaction
medium, cyclialkylation product 2a was obtained in a better
yield than that operated in pure water (entry 10). However, on
replacing phenol with more acidic 4-nitrophenol, the yield
of diol increased (entry 11). If water containing 0.2 equiv. of
acetic acid was used as the reaction medium, the amount of
diol further increased and the yield of cyclialkylation product
2a decreased to 12% (entry 12). This indicates the importance
of using a weak acid to ensure the cyclialkylation, in which the
arene acts as the nucleophile. Activation of epoxides by a
strong proton acid mainly provides the solvolysis product diol.
In 2008, Mayr’s research group reported that the
intermolecular ring-opening of epoxides with electron-rich
The cyclialkylation of (2R,3R)-2-((3,5-dimethoxyphenoxy)-
methyl)-3-phenyloxirane (1a) produces 3-chromanol which is
the core structure of many natural products. Lewis acid
catalyzed cyclialkylation using AuCl3/3AgOTf (2.5 mol%),
FeBr3 (10 mol%) or BF3ÁEt2O (30 mol%) gave 2a in 76%,
92%, and 79% yields respectively.2,3 The cyclialkylation of 1a
was firstly tested in refluxing water without any additive.
Although diol from the hydrolysis of epoxide was produced
in 45% yield, the reaction indeed gave the desired cyclialkylation
product 2a in 55% yield (Table 1, entry 5).5 In toluene,
acetone or acetonitrile, cyclialkylation did not occur, even
after prolonged refluxing. The reaction proceeded slowly in
methanol and 18% yield was obtained after 26 h. These
experiments clearly indicate that water at refluxing temperature
can activate epoxides. We reason that more acidic but less
nucleophilic solvents should perform better than water.
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071, China. E-mail: qujin@nankai.edu.cn;
Fax: +86-22-23499254; Tel: +86-22-23499247
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b926684d
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Table 2 HFIP-promoted intramolecular cyclialkylationa
heteroarenes such as indoles and pyrroles could take place in
refluxing TFE without additional catalyst. The reactions gave
moderate to excellent yields and excellent stereoselectivities.8
The ring-opening of epoxides with arenes is more important
and of general interest, but carrying out these reactions in
fluorinated alcohols has not been systematically studied.9
Encouraged by the high efficiency of the non-metal-mediated
cyclialkylation of 1a in refluxing HFIP, the scope of this
method was studied by varying the substituted groups on the
phenyl ring and the oxirane. Methoxy-substituted, tert-butyl-
substituted, unsubstituted, and halogen-substituted phenyl
rings were all good nucleophiles to react with the phenyl
substituted epoxides 1b–1f (Table 2, entries 1–6). Naphthalene
and halogen-substituted naphthalene 1g and 1h (entries 7 and 8)
were also good nucleophiles, providing high yields of
cyclialkylation products selectively at the a-position of
naphthalene. The cyclialkylations of enantiopure substrates
1b, 1c, 1d, and 1f were found to be stereospecific by comparing
the products’ optical rotation values with the reported data.
The cyclialkylations of enantiopure substrates 1e, 1g, and 1h
were also stereospecific since 99% enantiopure product was
formed as detected by chiral HPLC. The cyclialkylation of
2-[(3,5-dimethoxyphenoxy)phenylmethyl]oxirane 1i (entry 9)
is useful in particular because the reaction generates the core
structure of naturally occurring catechins.10 In previous
research, the combination of AuCl3/3AgOTf was too harsh
for this substrate and an improved catalytic system containing
thiourea/AuCl3/AgOTf was used to construct 2i in 65%
yield.11 The annulation of 1i in refluxing HFIP was slow but
clean due to the weak acidity of HFIP. Compound 2i was
obtained in 96% yield based on 53% conversion of the starting
material. Microwave irradiation was applied to this reaction,
but no positive effect was observed. This provides an
alternative process for synthesizing the biologically active
catechins. The dimethyl substituted epoxide 1j (entry 10)
reacted faster and gave a similar yield comparing with the
terminal dihydrogen substituted epoxide 1i (entry 9).
Yield
(%)
Entry Substrate
Product
Time
1
5 min 99
30 min 96
30 min 99
2
3
4
5
6
1 h
88
87
88
6 h
4.5 h
7
15 min 91
20 min 96
8
9
72 h
48 h
51
52
AuCl3/3AgOTf (5 mol%) or FeBr3/3AgOTf (10 mol%) can
also catalyze the intermolecular reaction between electron-rich
arenes and epoxides but only moderate yields can be
obtained.2,3 Mayr’s research group formerly tried the inter-
molecular reaction between anisole and styrene oxide in
refluxing TFE and isolated only solvent addition product.8
To test whether intermolecular Friedel–Crafts alkylation can
take place under these reaction conditions, we attempted the
reaction between 1,3,5-trimethoxybenzene and (R)-styrene
oxide in refluxing HFIP (Table 3). The reaction proceeded
quickly at the benzylic position of styrene oxide and gave 61%
yield of alkylation product 3a accompanied by 30% of HFIP
addition product (also at the benzylic position of styrene
oxide). The intermolecular reaction was also stereospecific
judged from the chiral HPLC analysis. When the above
intermolecular reaction was carried out in water, only 5%
alkylation product was formed along with 95% of diol.
When the nucleophilicity of the arene declines, the yield of
alkylation product decreases while the yield of solvolysis
product increases. 1,4-Dimethoxybenzene reacted with styrene
oxide, providing 35% of alkylation product 3c and 60% of
solvolysis product. For the reaction between anisole and
10
a
All reactions were conducted with 0.15 mmol of substrate in 5 mL of
refluxing HFIP; isolated yield.
styrene oxide, only 15% of alkylation product 3d was
obtained. The reaction between 1,3,5-trimethoxybenzene and
aliphatic propylene oxide proceeded slowly at the less-
substituted position of the epoxide and the conversion-based
yield of 3e was 96% after 48 h.
Water and fluorinated alcohols possess various special
properties (acid/base character, hydrogen bond forming
ability, high polarity, and high ionizing power) and thus the
contribution of each property to the reaction is worth discussing.
In the study of reactions between indoles and epoxides in
refluxing TFE, it was suggested that heterolytic cleavage of the
C–O bond was facilitated by electrophilic solvent assistance
(ESA) from the protic solvent TFE.8,12 This report also
emphasized the beneficial solvent effect of fluorinated alcohols
in respect to their high ionizing power and low nucleophilicity.
We also found that the reactions did not work in solutions of
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Table 3 HFIP-promoted intermolecular Friedel–Crafts alkylationa
state of the reaction could be stabilized well by the high
ionizing solvent HFIP.
Nucleophile
Epoxide Product
Time/h Yield (%)
In conclusion, 1,1,1,3,3,3-hexafluoroisopropanol can efficiently
promote the electrophilic aromatic substitution between
arenes and epoxides with high regio- and stereocontrol. This
non-metal-mediated Friedel–Crafts alkylation does not need
strict anhydrous conditions which are usually required for
Lewis acid catalyzed reactions. Removing low boiling point
(b.p. = 59 1C) and low viscosity HFIP by distillation affords
the product and HFIP can be recovered and reused. Water can
also promote the Friedel–Crafts alkylation although the diol
by-product is also formed, especially in the intermolecular
reactions. We believe that the unique catalytic effects of HFIP
and water demonstrated here will enable their further usage in
other Lewis acid catalyzed reactions.
0.5
0.5
61 (499% ee)
50b
0.5
0.5
48
35b
15b
96c
This work was financially supported by The National
Natural Science Foundation of China (20402007, 20772065),
Program for New Century Excellent Talents in University, the
111 Project (B06005) and the 863 Project of the Ministry of
Science and Technology of China (2006AA020502).
a
The reactions were conducted with nucleophiles (2.5 mmol) and
epoxides (0.5 mmol) in 2.5 mL of refluxing HFIP; isolated yield.
b
Racemic styrene oxide was used; the conversion of the reaction was
c
100% and the major by-product was hexafluoroisopropyl ether. The
ratio of propene oxide and 1,3,5-trimethoxybenzene was 1 : 1; 30%
conversion.
Notes and references
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oxirane.
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which suggested that the high polar and high ionizing reaction
medium was crucial.
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Water, fluorinated alcohols and phenol have a common
property in their acidic nature. The cyclialkylation of 1a is
more efficient in more acidic HFIP (pKa = 9.3) than in TFE
(pKa = 12.4). Similarly, a better result is obtained after the
addition of 20 mol% of phenol (pKa = 9.95) in water
(pKa = 15.7). We presume that the reactions carried out in
aqueous solution or fluorinated alcohols are acid-catalyzed.
We noticed that hydrogen bond forming mechanisms have
been proposed in other HFIP-promoted reactions.13 But in the
present studies, maximum reaction rates were reached in
refluxing water or refluxing fluorinated alcohols. Actually
the hydrogen bond donating ability of these solvents drops
as temperature rises owing to the fact that hydrogen-bond
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remarkable stabilizing effect for cationic species due to its high
polarizability and low nucleophilicity,15 the epoxide ring-opening
does not go through a discrete carbocation intermediate
because both intra- and intermolecular alkylation take place
with high stereocontrol and a total SN2 inversion is observed.
We assumed that water, fluorinated alcohols and phenol are
capable of activating epoxides by protonation (Scheme 1). The
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carbon–carbon bond are concerted.16 The polar transition
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Chem. Commun., 2010, 46, 2653–2655 | 2655