Catalytic Asymmetric Synthesis of 3-Hydroxy-3-trifluoromethyl Benzofuranones via Tandem Friedel-Crafts/Lactonization Reaction

Article abstract of DOI:10.1021/acs.orglett.5b02440

A highly enantioselective and regioselective chiral Lewis acid catalyzed tandem Friedel-Crafts/lactonization reaction is reported, providing direct access to plenty of 3-hydroxy-3-trifluoromethyl benzofuran-2-ones in up to 94% yields with up to >99% ee. Mechanistic study reveals that the interactions between the phenolic hydroxyl group and trifluoropyruvate are the most likely contributing factor to the high enantio- and regioselectivity. Optically pure (-)-BHFF can be obtained in gram-scale with 0.05 mol % catalyst, demonstrating the potentially utility of this method in medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.5b02440

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Synthesis of 3‑Hydroxy-3-trifluoromethyl
Benzofuranones via Tandem Friedel−Crafts/Lactonization Reaction
Hai Ren, Pan Wang, Lijia Wang,* and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A highly enantioselective and regioselective chiral
Lewis acid catalyzed tandem Friedel−Crafts/lactonization reac-
tion is reported, providing direct access to plenty of 3-hydroxy-3-
trifluoromethyl benzofuran-2-ones in up to 94% yields with up to
>99% ee. Mechanistic study reveals that the interactions between
the phenolic hydroxyl group and trifluoropyruvate are the most
likely contributing factor to the high enantio- and regioselectivity.
Optically pure (−)-BHFF can be obtained in gram-scale with 0.05
mol % catalyst, demonstrating the potentially utility of this method in medicinal chemistry.
Scheme 1. Catalytic and Asymmetric Tandem Friedel−
he 3,3-disubstituted benzofuran-2-one is a prominent
Tcommon structure, which exists in plenty of biologically
active and natural products.1 Recently, the 3-hydroxy-3-
trifluoromethyl substituted benzofuran-2-ones have attracted
increasing attention because of their remarkable medicinal and
pharmaceutical activities partly due to the unique properties of
the trifluoromethyl moiety.2 For example, 5,7-di-tert-butyl-3-
hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (BHFF) was
found to be a strikingly effective GABAB positive allosteric
modulator and was demonstrated to have therapeutic potential
to treat nervous system disorders.3 Notably, (−)-BHFF has
proven to be more robust than (+)-BHFF and rac-BHFF by in
vivo studies on Chinese hamsters.3a Among the methodologies
to establish 3-hydroxy-3-trifluoromethyl benzofuran-2-ones, the
tandem Friedel−Crafts/lactonization reaction represents a
direct access, which has been studied since the 1980s.4 In
most cases, harsh reaction conditions, for example, using a
strong organic acid as solvent at high temperatures, as well as a
stoichiometric amount of active species were required. The
reason is probably due to the complexing of the exposed
phenolic hydroxyl group with the Lewis acid catalysts and
poisoning the catalyst. Importantly, of specific interest is to
realize the enantio- and regiocontrol to obtain this targeted
structure. However, to date, the optically active ones can only
be accessed by resolution3a and no catalytic asymmetric method
has been reported. The establishment of efficient and reliable
methodologies to these optically active compounds with simple
and economical starting materials is in great demand.
Crafts/Lactonization
As the regioselectivity is usually poor in the reported tandem
Friedel−Crafts/lactonization reactions,4b,c 2,4-di-tert-butylphe-
nol 1a was first chosen as a model substrate to avoid this
t
problem. Initially, 10 mol % of BuBOX(L1)/Cu(OTf)2 was
employed as the catalyst since it proved to be powerful in the
asymmetric Friedel−Crafts reactions of electron-rich aromatics
with trifluoropyruvates5 by Jørgensen and coworkers.6 Un-
fortunately, the desired product was obtained in only 27% yield
with 40% ee in dichloromethane even after running the reaction
for 16 h at room temperature (Table 1, entry 1). The amount
of trifluoropyruvates was increased from 1.1 to 11 equiv to
speed up the optimization. In this case, the yield of product was
greatly enhanced to 83% and the ee value was also improved
from 40% to 53% (entry 2). Considering that ligands bearing
sterically different backbones may primarily influence the
enantioselectivity,7 we turned to investigate the effects of
other ligands. When L2 and L3 were used, the lactone product
was formed with poor levels of enantioselectivity (entries 3 and
4). A better result was achieved by using ligand L4 resulting in
77% ee together with a 93% yield (entry 5). Side-armed
oxazoline ligand L5 failed to enhance the enantiocontrol (entry
Recently, we found that a simple chiral BOX/Cu(II) catalyst
exhibited high efficiency in this tandem reaction, giving a broad
range of 3-hydroxy-3-trifluoromethyl benzofuran-2-ones with
high levels of enantioselectivity (Scheme 1). In particular,
optically active (−)-BHFF was synthesized in gram-scale with
0.05 mol % catalyst. In this letter, we wish to report our efforts
on this subject.
Received: August 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02440
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Table 2. Substrate Scope with Ethyl Trifluoropyruvate
b
c
entry
R
t (h) yield (%)
ee (%)
94
1
2
3
4
5
2,4-di-tBu (1a)
25
32
94
80
81
88
94
75
51
94
83
67
2-tBu, 4-Me (1b)
2-tBu, 4-OMe (1c)
2-tBu, 4-Et (1d)
2,4-ditertpentyl (1e)
2,4-di-iPr (1f)
96
95
95
94
99
>99
92
32
48
24
d
6
48
d
7
d
2,4-di-Me (1g)
96
,
,
e
e
8
9
2,4-di(2-phenyl)propyl (1h)
2-tBu (1i)
14
d
120
120
85 (>99/1)
90 (95/5)
d,e
10
2-phenyl (1j)
a
temp
yield
b
ee
The reactions were carried out at −78 °C under N2 atmosphere:
Cu(OTf)2 (0.04 mmol), L4 (0.04 mmol), DCM (4.0 mL), 1/2b = 1/
c
entry
L
M
(°C)
t (h)
(%)
(%)
b
c
d
1
L1
L1
L2
L3
L4
L5
L6
L7
L4
L4
L4
L4
L4
L4
L4
L4
L4
Cu(OTf)2
rt
16
4
27
83
94
95
93
94
94
93
93
86
93
93
75
92
93
94
94
40
53
45
47
77
69
11
30
76
56
58
0
1.5 (1, 0.40 mmol). Isolated yield. Determined by HPLC analysis on
chiral stationary phases; in parentheses are regioselectivity of ortho/
para alkylation products. The reaction was carried out at room
2
Cu(OTf)2
rt
d
3
Cu(OTf)2
rt
4
e
temperature. 2.5 equiv of 2b were used.
4
Cu(OTf)2
rt
4
5
Cu(OTf)2
rt
4
6
Cu(OTf)2
rt
3
7
Cu(OTf)2
rt
3
entries 1−5). When substrate 1f bearing isopropyl groups at
both the ortho and para position was subjected to the reaction,
the reactivity decreased while the enantioselectivity can reach
up to 99% even with a change to room temperature (entry 6).
The presence of a less hindered methyl group at both the ortho
and para position led to a decreased yield but excellent
enantioselectivity (entry 7). Substrate 1h was also tolerated in
the reaction, giving an excellent yield and enantioselectivity
(entry 8). Further exploration was carried out in terms of the
regioselectivity with only one substituent on the ortho position
of the phenyl ring. To our delight, a Friedel−Crafts reaction
proceeds regiospecifically with >99/1 regioselectivity with
substrate 1i and 95/5 regioselectivity with 1j of ortho/para
alkylation products respectively, giving the lactonization
products in good yields and high levels of enantioselectivity
(entries 9−10).
8
Cu(OTf)2
rt
3
9
Cu(ClO4)2·6H2O
Cu(SbF6)2
Ni(ClO4)2·6H2O
Fe(OTf)3
rt
2
10
11
12
13
14
15
rt
2
rt
2
rt
2
Mg(ClO4)2·6H2O
Cu(OTf)2
rt
15
8
12
85
90
94
94
−40
−78
−78
−78
Cu(OTf)2
8
e
16
e,f
Cu(OTf)2
25
25
17
Cu(OTf)2
a
The reactions were carried out under a N2 atmosphere: Lewis acid
(0.040 mmol), L (0.048 mmol), 0.2 M, DCM (2.0 mL), 1a (0.40
b
c
mmol), 2a (4.40 mmol). Isolated yield. Determined by HPLC
d
e
analysis on chiral stationary phases. M/L = 1/1.2, 1.1 equiv of 2. M/
f
L = 1/1, 1.5 equiv of 2, 0.1 M, DCM (4 mL). 2b was used.
The efficiency of this tandem reaction was further
investigated with phenols substituted with other alkyl groups.
It was observed that phenols with no substituents at the ortho
position were less reactive, which required a higher temperature
and longer reaction time. Methyl trifluoropyruvate was found to
give a better yield than the ethyl trifluoropyruvate, probably
because the methyl ester is more reactive than the ethyl ester in
the lactonization step. For all of these substrates, the levels of
enantioselectivity still remain excellent despite moderate yields
in some cases (Table 3, 1k−1v). Notably, phenol without any
activating substituent can also react smoothly with excellent
enantio- and regioselectivity (1o). The absolute configuration
of the product 3a was determined by comparing its optical
rotations with the literature value;2b other products were
assigned by analogy.
The practical utility of the current reaction was demonstrated
by its application to large scale synthesis of optically active
(−)-BHFF (Scheme 2), a remarkable effective GABAB positive
allosteric modulator and a key intermediate in biologically
active molecules. Significantly, the catalyst loading can be
lowered to 0.05 mol % under the optimized reaction
conditions, giving (−)-BHFF in 82% yield with 90% ee. The
6), and no further improvements on enantioselectivity were
engendered by using ligands L6−L7 (entries 7−8). Attempts to
improve the enantioselectivity by further screening of Lewis
acids were not successful (entries 10−13). The ee value can be
slightly increased under a reduced reaction concentration,
whereas studies on other solvents could not improve the
selectivities.8 Remarkably, the level of enantioselectivity was
increased significantly when lowering the temperature to −40
°C or even to −78 °C, while still maintaining high reactivity
(85% ee and 90% ee, entries 14 and 15). Encouragingly, further
study showed that 94% ee together with a 94% yield could be
obtained even when reducing the amount of trifluoropyruvate
from 11 to 1.5 equiv under optimized conditions (entry 16).
Changing methyl trifluoropyruvate to ethyl trifluoropyruvate
gave a similar result (entry 17).
Under the optimized conditions, the substrate scope of the
current protocol was investigated next. As shown in Table 2,
substrates 1a−1e with electron-rich subustituents at the para
position on the aromatic ring, bearing a tert-butyl group on the
ortho position at the same time, reacted smoothly. Excellent
levels of enantioselectivity and yields were obtained (Table 2,
B
DOI: 10.1021/acs.orglett.5b02440
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Substrate Scope with Methyl Trifluoropyruvate
Scheme 3. Control Experiments and Proposed Reaction
Pathway
a
The reactions were carried out at rt under a N2 atmosphere:
Cu(OTf)2 (0.08 mmol), L4 (0.08 mmol), 1/2a = 1/1.5 (1, 0.80
b
mmol), DCM (8.0 mL). Isolated yield; yield in parentheses was
determined by 19F NMR with PhCF3 as internal standard.
c
Determined by HPLC analysis on chiral stationary phases; in
parentheses are regioselectivity of ortho/para alkylation products
d
determined by 19F NMR with PhCF3 as internal standard. The
e
f
reaction was carried out at 40 °C. 2.5 equiv of 2a were used. 0.2 M,
0.4 mmol scale.
Scheme 2. Gram-Scale Synthesis of Optically Active
(−)-BHFF
between the hydroxyl group and trifluoropyruvates, followed by
an intramolecular transesterification process.
In summary, a highly enantioselective Lewis acid catalyzed
tandem Friedel−Crafts/lactonization tandem reaction has been
developed, enabling a direct asymmetric synthesis of plenty of
3-hydroxy-3-trifluoromethyl benzofuran-2-ones from readily
available trifluoropyruvates and substituted phenols with up
to >99% ee. To the best of our knowledge, this is the first
example of a catalytic asymmetric reaction of its version.
Mechanistic study suggested that the C2-alkylating pathway is
favored with phenolic hydroxyl as the directing group, followed
by a lactonization process. Moreover, the newly developed
methodology can be applied to gram-scale synthesis of optically
active (−)-BHFF with excellent enantioselecitvity with merely
0.05 mol % catalyst loading, which makes it potentially useful in
the industrial synthesis of other medicinal and pharmaceutical
compounds.
corresponding product can be recrystallized to >99% ee in 62%
yield.
The current protocol showed excellent regioselectivity. To
fully understand the selectivity, several control experiments
have been carried out. As shown in Scheme 3, we had observed
minor amounts of alkylation product on the para (C4) position
with 95/5 regioselectivity in the case of phenol (eq 1).
However, when anisole was subjected to the optimal reaction
conditions, only the C4-alkylating product was observed with
merely 51% ee (eq 2). Similarly, the more nucleophilic sodium
phenate gave the C4-alkylating product only in 15% yield with
2% ee (eq 3).
These results showed that the free hydroxyl group in the
phenol plays an important role in the regioselectivity. It was
also found that the C4-alkylated product 3o′ could not be
transformed into the C2-alkylated 7 or the desired product 3o
(eq 4), suggesting that the Friedel−Crafts alkylation is not a
reversible process in the present reaction system. Based on
these observations, combined with the fact that we have
isolated minor nonlactonized intermediates in some substrates,9
we proposed that the current reaction proceeds via a two-step
process as shown in (eq 5). The first step is a Friedel−Crafts
reaction in which the selectivity is directed by the H-bond
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02440.
Condition optimization, experiment procedures, and
product characterization (PDF)
C
DOI: 10.1021/acs.orglett.5b02440
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tangy@sioc.ac.cn.
*E-mail: wanglijia@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Sciences Foundation of China (Nos. 21121062,
21432011, and 21272250), the National Basic Research
Program of China (973 Program) (2015CB856600), and the
Chinese Academy of Sciences.
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DOI: 10.1021/acs.orglett.5b02440
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