Enantioselective carbonyl-ene reactions of trifluoropyruvate in ionic liquid via a recyclable indium(III)-pybox complex

Article abstract of DOI:10.1002/adsc.201000170

A highly enantioselective carbonyl-ene reaction of trifluoropyruvate catalyzed by a recyclable indium(III)-pybox complex in ionic liquid afforded trifluoromethyl-containing tertiary homoallylic alcohols with excellent yields (up to 98%) and enantioselecti

Full text of DOI:10.1002/adsc.201000170

UPDATES
DOI: 10.1002/adsc.201000170
Enantioselective Carbonyl-Ene Reactions of Trifluoropyruvate in
Ionic Liquid via a Recyclable Indium(III)-Pybox Complex
U
Jun Feng Zhao,a Boon Hong Tan,a Ming Kui Zhu,a Teguh Budiono W. Tjan,a
and Teck Peng Loha,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371
Fax : (+65)-6791-1961; e-mail: teckpeng@ntu.edu.sg
Received: March 5, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000170.
Abstract: A highly enantioselective carbonyl-ene
reaction of trifluoropyruvate catalyzed by a recycla-
ene reaction of trifluoropyruvate catalyzed by a pow-
erful InACTHNGUETRNNU(G III)-pybox complex, which was designed
ble indium
N
based on the counterion effect.[7] Regarding the prac-
tical, economical and environmental factors and bio-
logical importance of the products, we herein present
forded trifluoromethyl-containing tertiary homoal-
lylic alcohols with excellent yields (up to 98%) and
enantioselectivities (up to 98% ee). Notably, this
catalytic system can be recycled up to seven cycles.
the InACHTNUGRTNEUNG
(III)-pybox complex[8] catalyzed, highly enantio-
selective ketone-ene reactions of trifluoropyruvates
by using ionic liquid as the solvent, which enable the
easy recycle of the chiral catalyst.
Recently, our laboratory has been interested in
using ionic liquid as an alternative to conventional or-
ganic solvent.[9] Employing ionic liquid as reaction
medium has many advantages among which the most
important one is the easy isolation of product by
Keywords: asymmetric catalysis; carbonyl-ene reac-
tion; indium; ionic liquids
Organofluorine compounds have attracted much at- simple extraction, which enables recycling of the ionic
tention in many scientific disciplines in view of the liquid containing the chiral catalyst.[10] As far as we
unique physical and biological properties of fluo- know, no asymmetric carbonyl-ene reaction of tri-
rine.[1] Among them, CF3-containing compounds are fluoropyruvate in ionic liquid has been reported.[11]
of great interesting due to the unique properties, such Considering the stability and recyclability of the In-
as lipophilicity, stability, and strong electronegativity
of the CF3 group. Introduction of CF3 groups often in- to carry out the ketone-ene reaction in ionic liquid.
duces considerable changes in the chemical, physical, The catalyst was prepared by mixing indium(III) chlo-
(III)-pybox complex in ionic liquid,[12] we attempted
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
and physiological properties of the parent com- ride, pybox (+)-1 and 4 ꢀ molecular sieves in a solu-
pounds.[2] Therefore, synthetic methods for introduc- tion of 1,2-dichloroethane (DCE) and stirring for
ing the trifluoromethyl group into an organic com- 20 min at room temperature. Then, AgSbF6 was
pound selectively have developed into an important added to replace the anion of the parent InACHTUNGTRENNUNG(III)-
field of chemistry.[3] The asymmetric carbonyl-ene re- pybox complex. After stirring for another 20 min,
action of trifluoropyruvate,[4] one type of ketone-ene ionic liquid [bmim]PF6 was added, followed by se-
reaction, is an effective methodology for constructing quential addition of a-methylstyrene and methyl tri-
optically active tertiary homoallylic alcohols, contain- fluoropyruvate. To our delight, the carbonyl-ene reac-
ing a trifluoromethyl group, which are important tion proceeded smoothly and afforded the enantioen-
building blocks for pharmaceuticals and agrochemi- riched tertiary allylic alcohol in 95% yield and 93%
cals. To our surprise, however, there are only few suc- ee (Table 1, entry 1). Among the ionic liquids
cessful examples of asymmetric ketone-ene reac- screened, [hmim]PF6 proved to be the best choice of
tions[4,5] compared to the extensive studies of asym- solvent (Table 1, entry 2).
metric aldehyde-ene reactions.[6] Thus far, the ketone-
We next examined the generality of this methodol-
ene reaction still remains as a challenge. We have re- ogy and the results are summarized in Table 2. As
cently developed a highly enantioselective carbonyl- shown in Table 2, the asymmetric ketone-ene reac-
Adv. Synth. Catal. 2010, 352, 2085 – 2088
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2085

Jun Feng Zhao et al.
UPDATES
Table 1. Optimization studies.[a]
Table 2. (Continued)
Entry Product [4a–n]
Time
[h]
Yield[b]
[%]
ee[c]
[%]
97
(95)
6
7
4 (144) 91 (90)
98
(91)
7 (48)
4 (3)
97 (97)
80 (91)
96
(95)
8
Entry
Ionic liquid
Time [h]
Yield[b] [%]
ee[c] [%]
80
(85)
1
2
3
4
U
1
1
1
24
24
1
95
96
94
trace
trace
95
93
96
92
–
–
96
9
72 (72) 74 (86)
97
(95)
10
11[d]
20 (3)
1 (2)
3 (6)
91 (99)
85 (99)
78 (79)
5
6[d]
[a]
55
(64)
[b]
[c]
[d]
98
(96)
12[e]
13[f]
98
(98)
43 (48) 98 (95)
Table 2. InACHTUNGTRENNUNG(III)-pybox complex-catalyzed aymmetric carbon-
yl-ene reactions of methyl trifluoropyruvate with various
olefins in ionic liquid.[a]
92
(98)
14
43 (3)
98 (94)
[a]
Unless otherwise noted, reactions were carried out on a
0.3 mmol scale with 2 equiv. of trifluoropyruvate in a
mixture of 0.5 mL [hmim]PF6 and 0.5 mL 1,2-dichloro-
ethane (DCE) at room temperature; the results in paren-
theses are for the reactions carried out in DCE.[7]
Isolated yield.
The ee values were determined by chiral-phase HPLC or
GC analysis.
5 mol% of catalyst loading was used.
Entry Product [4a–n]
Time
[h]
Yield[b]
[%]
ee[c]
[%]
[b]
[c]
[d]
[e]
[f]
96
(95)
1
2
3
4
5
1 (3)
1 (3)
1 (3)
95 (99)
92 (98)
93 (97)
90 (56)
91 (92)
Excess of isobutene was used.
This reaction was carried out at 08C.
95
(94)
tions of trifluoropyruvate proceeded smoothly to give
the products with excellent yields and enantioselectiv-
ities. In addition, most of the reactions carried out in
ionic liquid proceeded faster than those carried out in
pure organic solvent with comparable or better yields
and enantioselectivities. Similar to the reactions car-
ried out in pure organic solvent, significant electronic
and steric effects were also observed in this system.
An electron-withdrawing group on the phenyl ring of
substituted a-methylstyrene prolonged the reaction
time (Table 2, entries 4–7). The position of the substi-
94
(94)
162
(240)
97
(87)
97
(92)
5 (72)
2086
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2085 – 2088

Enantioselective Carbonyl-Ene Reactions of Trifluoropyruvate in Ionic Liquid
tuted group also has an effect on the reaction efficien- yields; (iii) the chiral InACTHUNRTGNEUNG(III)-pybox complex in ionic
cy. Due to steric effect, either an electron-withdraw- liquid could be recycled up to seven times with reten-
ing or an electron-donating group at the ortho posi- tion of excellent catalytic efficiency; (iv) the opera-
tion led to lower yields and enantioselectivities tionally simple procedure will make this catalytic
(Table 2, entries 4 and 9). The lowest enantioselectivi- system more attractive for industrial as well as aca-
ty observed in 4k might be due to the more reactive demic laboratories. Studies on further applications of
nature of substrate 3k (Table 2, entry 11).
this catalytic system to other organic transformations
In terms of cost-effectiveness, the recyclability of are underway in our laboratory.
the chiral catalyst is a very important and a challeng-
ing task for industry. Therefore, we further investigat-
ed the recyclability of the In
using the ketone-ene reaction of methyl trifluoropyru-
G
vate and a-methylstyrene as the model reaction and General Procedure for Carbonyl-Ene Reactions of
the results are listed in Table 3. After the reaction Alkenes with Trifluoromethylpyruvate Catalyzed by
was completed, the reaction mixture was extracted InACHTNUGTRENUNG(III)-Pybox complex in the Ionic Liquid [hmim]PF6
with hexane (5ꢂ5 mL) to leave the ionic liquid
[hmim]PF6 containing the chiral InACTHNUTRGNE(NUG III)-pybox com-
plex, which can be used directly for the next cycle. It
is noteworthy that this catalytic system can be reused
for up to seven cycles with retention of excellent cata-
lytic efficiency.
In an oven-dried, 5-mL round-bottom flask equipped with a
stirring bar, indium(III) chloride (6.66 mg, 0.03 mmol),
AHCTUNGTRENNUNG
pybox (+)-1 (14.4 mg, 0.036 mmol) and 4ꢀ molecular sieves
(100 mg) were stirred in a solution of DCE (0.5 mL) for
20 min at room temperature. To the above mixture, silver
hexafluoroantimonate (AgSbF6) (20.64 mg, 0.06 mmol) was
added in one portion and stirred for another 20 min. To the
pre-prepared catalyst in 1,2-dichloroethane (DCE), ionic
liquid [hmim]PF6 (0.5 mL) was added and stirred at room
temperature for 10 min. Then the alkene (0.3 mmol,
1 equiv.) and trifluoromethylpyruvate (93.6 mg, 0.6 mmol,
2 equiv.) were added using a syringe. The mixture was
stirred until the alkene had been consumed completely as
indicated by TLC analysis. The crude product was loaded di-
rectly onto a silica gel column and purified by flash column
chromatography to obtain the enantioenriched tertiary ho-
moallylic alcohol.
In summary, we have developed a chiral InACTHNUTRGNEUG(N III)-
pybox complex-catalyzed, highly enantioselective
ketone-ene reaction of trifluoropyruvate in ionic
liquid. This methodology has many advantages such
as: (i) the moisture tolerant catalyst, which is easily
prepared from commercially available chemicals, ren-
ders strict anhydrous conditions unnecessary; (ii) CF3-
containing homoallylic alcohols, important building
blocks of pharmaceuticals and agrochemicals, can be
obtained with excellent enantioselectivities and
Procedure for Recycle of In
Ionic Liquid ([hmim]PF6)
ACHTUNGERTN(NUNG III)-Pybox Complex in
Table 3. Recyclability study.[a]
After the reaction in ionic liquid was completed, the reac-
tion mixture was extracted with hexane (5ꢂ5 mL) to afford
the crude ketone-ene product. 0.5 mL of DCE was added to
the ionic liquid residue for the next run under identical reac-
tion conditions. This catalytic system can be recycled for
seven times and give the ketone-ene product in 96% yield
and 94% ee for the last run.
Cycle
Time [h]
Yield[b] [%]
ee[c] [%]
Acknowledgements
1
2
3
4
5
6
7
1
1
1
1
1
1.5
1.5
95
97
93
96
95
98
96
96
95
96
96
95
94
94
We gratefully acknowledge Nanyang Technological Universi-
ty and Ministry of Education Academic Research Fund Tier
2 (No. T207B1220RS) for the funding of this research.
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Unless otherwise noted, reactions were carried out on a
0.3 mmol scale with 2 equiv. of trifluoropyruvate in a
mixture of 0.5 mL [hmim]PF6 and 0.5 mL 1,2-dichloro-
ethane (DCE) at room temperature.
Isolated yield.
The ee values were determined by chiral-phase HPLC.
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2088
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2085 – 2088