Highly enantioselective α-aminoxylation of aldehydes and ketones in ionic liquids

Article abstract of DOI:10.1021/jo061507g

As the first example for the synthesis of optically active α-hydroxyaldehydes and α-hydroxyketones in ionic liquids, we applied RTILs into L-proline catalyzed direct enantioselective α-aminoxylation of both aldehydes and ketones successfully. This protoco

Full text of DOI:10.1021/jo061507g

interests on proline catalyzed direct asymmetric R-aminoxylation
of aldehydes or ketones for the synthesis of optically active
R-hydroxyaldehydes and R-hydroxyketones. In 2003, Zhong,7
MacMillan,8 and Hayashi et al.9a independently found that
L-proline was able to catalyze the direct asymmetric R-ami-
noxylation of aldehydes with excellent enantioselectivities. Then
Hayashi9b and Cordova et al.1 simultaneously reported that
ketones underwent proline catalyzed R-aminoxylation to give
2-aminoxy ketones with excellent enantioselectivities, which
further reacted with copper sulfate to generate enantiopure
R-hydroxyketones.
Highly Enantioselective r-Aminoxylation of
Aldehydes and Ketones in Ionic Liquids
Kun Huang, Zhi-Zhen Huang,* and Xin-Liang Li
School of Chemistry and Chemical Engineering, Nanjing
UniVersity, Nanjing 210093, P. R. China
huangzz@nju.edu.cn.
In recent years, ionic liquids played increasingly important
roles in organic synthesis, because they displayed many
advantages over common organic solvents, such as nonvola-
tilities, easy recycling, immiscibilities with many organic
solvents, and good solvating properties for both inorganic and
organic compounds.10,11 A lot of organic,10 organometallic,10,11
and biocatalyzed reactions11b,12 have been investigated in ionic
liquids. The application of ionic liquids in asymmetric synthesis
is receiving more and more attention. Several uses of ionic
liquids in catalytic asymmetric reactions with good yields, high
enantioselectivities, or other advantages are particularly attrac-
tive. In 2002, Toma et al. reported that proline-catalyzed
asymmetric aldol reaction can be performed smoothly in 1-butyl-
3-methyl imidazolium hexafluorophosphate [bmim][PF6] in 46-
94% yields with 47-82% ee.13 In 2004, Li et al. disclosed the
asymmetric aminohalogenation of functionalized alkenes in
imidazolium tetrafluoroborate [bmim][BF4] with good yields and
diastereoselectivities.14 In 2005, Jiang et al. found that in the
presence of L-prolinamide, the asymmetric aldol reaction of
aldehydes with unmodified ketones can be conducted in
imidazolium ionic liquids with excellent enantioselectivities.15
However, to the best our knowledge, there is no report on the
application of ionic liquids in the asymmetric synthesis of
optically active R-hydroxyaldehydes and R-hydroxyketones,
including the L-proline catalyzed direct asymmetric aminoxy-
lations of aldehydes and ketones. Considering that the L-proline
catalyzed aminoxylations are performed in harmful solvents
(such as CH3CN, CHCl3, DMSO, C6H6, etc.) and that L-proline,
a metal-free catalyst, contains strong polar bonds, we planned
to investigate whether room temperature ionic liquids (RTILs)
could be used as user- and eco-friendly solvents, and simulta-
neously, as immobilizing media for the recycling of chiral
catalyst in the aminoxylation reaction to produce optically active
ReceiVed July 20, 2006
As the first example for the synthesis of optically active
R-hydroxyaldehydes and R-hydroxyketones in ionic liquids,
we applied RTILs into L-proline catalyzed direct enantiose-
lective R-aminoxylation of both aldehydes and ketones
successfully. This protocol features a number of advantages,
such as recycling of green solvents and chiral organocatalyst,
high yields, excellent enantioselectivities, short reaction
times, and broad substrate scope.
Optically active R-hydroxyaldehydes and R-hydroxyketones
are important building blocks in organic synthesis. These
structure units are commonly found in biologically active natural
products.1 Recently, extensive researches have been carried out
to find diastereoselective and enantioselective routes for their
synthesis.2 Several methods using catalytic asymmetric reactions
are particularly useful, which include the Sharpless asymmetric
dihydroxylation of enol ethers,3 the asymmetric epoxidation of
silyl enol ethers with a chiral dioxirane,4 and the asymmetric
epoxidation of enol ethers with a chiral Mn-Salen catalyst.5
Most of these synthetic methods require multiple procedures.
On the other hand, proline has drawn much attention because
of its excellent behavior as chiral organocatalyst in many
asymmetric reactions.6 Very recently, there have been great
(7) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247.
(8) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan; D. W. C. J.
Am. Chem. Soc. 2003, 125, 10808.
(9) (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron
Lett. 2003, 44, 8293. (b) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2004, 43, 1112.
(10) (a) Welton, T.; Chem. ReV. 1999, 99, 2071. (b) Dupont, J.; de Souza,
R. F.; Suarez, P. A. Z. Chem. ReV. 2002, 102, 3667. (c) Deetlefs, M.;
Seddon, K. R. Chim Oggi 2006, 24, 16.
(11) (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772. (b) Gordon, C. M. Appl. Catal., A 2001, 222, 101.
(12) Sheldon, R. A.; Lau, R. M.; Sorgedrager, M. J.; van Rantwijk, F.;
Seddon, K. R. Green Chem. 2002, 4, 147.
(1) Bogevig, A.; Sunden, H.; Cordova, A. Angew. Chem., Int. Ed. 2004,
43, 1109.
(2) Davis, F. A.; Chen, B. C. In Houben-Weyl: Methods of Organic
Chemistry; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
Eds.; Georg Thieme: Stuttgart, Germany, 1995; Vol. E21, p 4497.
(3) Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.; Sharpless,
K. B. J. Am. Chem. Soc. 1993, 115, 8463.
(4) Adam, W.; Fell, R. T.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahe-
dron: Asymmetry, 1998, 9, 397.
(5) Adam, W.; Feli, R. T.; Stegmann, V. R.; Saha-Moller, C. R. J. Am.
Chem. Soc. 1998, 120, 708.
(6) (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102. (b) Nothrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152. (c) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2003, 42, 2785.
(13) Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E.
Chem. Commun. 2002, 2510.
(14) Xu, X.; Kotti Saibabu, R. S. S.; Liu, J.; Cannon, J. F.; Headley, A.
D.; Li, G. Org. Lett. 2004, 6 (26), 4881.
(15) Guo, H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem.
Commun. 2005, 1450.
10.1021/jo061507g CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/21/2006
8320
J. Org. Chem. 2006, 71, 8320-8323

TABLE 1. L-Proline-Catalyzed Direct Asymmetric r-Aminoxylation of Propanal or Cyclohexanone in Various RTILs
catalyst
(mol %)
time
(min)
yield of 1g
yield of 2a
ee of 1g
ee of 2a
entry
R
R1
RTILa
(%)b
(%)b
(%)c
(%)c
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
Me
Me
Me
Me
Me
Me
Me
Me
Me
[bmim][BF4]
[bmim][PF6]
[pmim][BF4]
[pmim][PF6]
[btpy][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
[bmim][PF6]
[pmim][BF4]
[btpy][BF4]
20
20
20
20
20
10
5
8
8
8
8
94
91
92
85
79
92
88
79
64
99
98
98
97
98
98
98
98
98
8
10
15
120
300
15
40
15
45
15
15
1
9
0.5
20
10
20
10
20
20
10
11
12
13
14
15
89
81
88
80
88
82
>99
>99
>99
>99
>99
>99
a pmim ) propylmethylimidazolium, btpy ) butylpyridinium. b Isolated yield. c Determined by chiral HPLC with a Chiralpak AD-H column.
hydroxyaldehydes and hydroxyketones with high yields and
excellent enantioselectivities.
aminoxy ketone 1g in good yields with excellent enantioselec-
tivities (>99% ee) (entries 10-15, Table 1).
Initially, 1-butyl-3-methyl imidazolium tetrafluoroborate [bmim]-
[BF4], which is one of the most common RTILs, was chosen
as a solvent in the L-proline catalyzed direct asymmetric
R-aminoxylation of aldehyde. We were pleased to find that using
L-proline as a chiral organocatalyst, propanal could undergo
R-aminoxylation with nitrosobenzene quickly (8 min) and
completely in ionic liquid [bmim][BF4] at room temperature
(Table 1). Because the O-regioselective addition product 1a is
labile on silica gel for column chromatography, it had to be
converted into the more stable 2-aminoxy alcohol 2a by the
successive treatment with sodium borohydride. Our experiment
showed that after the one pot reaction, (2R)-2-aminoxy alcohol
2a was isolated in excellent yield (94%) with excellent
enantioselectivity (99% ee) (entry 1, Table 1). Further investiga-
tion demonstrated that the L-proline catalyzed direct asymmetric
R-aminoxylation of propanal proceeded smoothly in various
RTILs at room temperature, affording desired (2R)-2-aminoxy
alcohol 2a in good to excellent yields (79%-94%) with
excellent enantioselectvities (97-99% ee). As shown in Table
1, the best RTILs for this reaction are ionic liquid [bmim][BF4]
and [bmim][PF6]. The effects of the catalyst amount on yield
and enantioselectivity were also studied. Experimental results
showed that the catalyst loading had no significant effect on
enantioselectivity even when the reaction was performed in 0.5
mol % proline (Table 1). However, a too small amount of
catalyst would lead to a decrease of yields (entries 8 and 9,
Table 1). On the basis of the above results, the best catalyst
loading for yield and enantioselectivity of the aminoxylation
reaction of propanal was 20 mol %. Moreover, we studied
L-proline catalyzed direct R-aminoxylation of ketones in ionic
liquids. In this experiment, cyclohexanone was selected as a
model ketone. It was found that in the presence of 20 mol % of
L-proline, cyclohexanone could also undergo the asymmetric
aminoxylation reaction smoothly with nitrosobenzene in various
ionic liquids at room temperature, giving the desired (2R)-2-
Then, various aldehydes and ketones were examined in the
asymmetric R-aminoxylation reaction with nitrosobenzene in
ionic liquid [bmim][BF4]. The experimental results showed that
all of the aldehydes or ketones could undergo the L-proline direct
aminoxylation smoothly and quickly (10-30 min) in ionic liquid
[bmim][BF4] at room temperature, affording the desired (2R)-
2-aminoxy alcohols 2a-f or (2R)-2-aminoxy ketones 1g-i in
moderate to excellent yields with excellent enantioselectivities
(Table 2). This suggests that the R-aminoxylation reaction in
ionic liquid [bmim][BF4] has broad substrate scope. As shown
in Table 1 and Table 2, the reaction of cyclohexanone in ionic
liquids is faster than that in common organic solvents, where
5-12 h are reported to be required.9b Moreover, the yields of
(2R)-2-aminoxy alcohols 2a-f or (2R)-2-aminoxy ketones 1g-i
were significantly improved in ionic liquid [bmim][BF4], as
compared to that in common organic solvents.1,7-9
With the success of the R-aminoxylation reaction in ionic
liquid, we continued our investigation in exploring the recy-
clability of ionic liquid and chiral catalyst owing to its
importance from an industrial perspective. The L-proline
catalyzed R-aminoxylation of propanal with nitrosobenzene in
ionic liquid [bmim][BF4] was chosen as a model. After the
aminoxylation reaction was completed at room temperature, the
reaction mixture was extracted with ethyl ether several times
to collect R-aminoxylation product and to keep the [bmim][BF4]
containing L-proline. 1HNMR indicated that there was no
R-aminoxylation product in the ionic liquid layer after the
extraction with ethyl ether. The ether layer was treated with
sodium borohydride to form (2R)-2-aminoxy alcohol 2a, and
1
the H NMR of crude product 2a indicated the absence of
L-proline. The recovered ionic liquid immobilizing L-proline was
used in the R-aminoxylation again, and we found that the desired
(2R)-2-aminoxy alcohol 2a was still obtained in excellent yield
(92%) with excellent enantioselectivity (98% ee) (entry 2, Table
3). Then, the recycling of ionic liquid and chiral catalyst in the
J. Org. Chem, Vol. 71, No. 21, 2006 8321

TABLE 2. L-Proline Catalyzed Direct r-Aminoxylation of Various Aldehydes and Ketones in [Bmim][BF4]a
time
(min)
yield of 1
yield of 2
ee of 1
ee of 2
entry
R
R1
product
(%)b
(%)b
(%)c
(%)c
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
Et
n-Pr
i-Pr
n-Bu
Bn
10
10
10
10
10
10
15
15
30
2a
2b
2c
2d
2e
2f
1g
1h
1i
94
89
84
93
79
85
99
98
97
>99
95
>99
(CH2)4
CH2CH2OCH2
CH2CH2NBnCH2
89
85
68
>99
99
>99
a Using 20 mol % L-proline. b Isolated yield. c Determined by chiral HPLC with a Chiralpak AD-H column.
TABLE 3. Recycling Use of [Bmim][BF4] and L-Proline in the Direct Asymmetric r-Aminoxylation of Propanal or Cyclohexanonea
recycling
time
time
(min)
yield of 1gb
yield of 2ab
ee of 1gc
(%)
ee of 2ac
(%)
entry
R
R1
(%)
(%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
Me
Me
Me
Me
Me
Me
1
2
3
4
5
6
1
2
3
4
5
6
10
10
10
10
12
12
15
15
15
15
15
15
94
92
88
86
85
83
99
98
98
97
97
96
89
89
87
86
82
81
>99
>99
>99
>99
99
9
10
11
12
99
a Using 20 mol % L-Proline. b Isolated yield. c Determined by chiral HPLC with a Chiralpak AD-H column.
direct R-aminoxylation of cyclohexanone was also studied. After
the aminoxylation reaction was finished, the reaction mixture
was extracted with ethyl ether and the ionic liquid [bmim][BF4]
containing L-proline could also be recovered quantitatively. We
employed the recovered ionic liquid immobilizing L-proline in
the R-aminoxylation reaction and discovered that the desired
(2R)-2-aminoxy ketone 1g was also obtained in equally good
yield (89%) with excellent enantioselectivity (>99% ee) (entry
8, Table 3). These recycling processes of R-aminoxylation of
both propanal and cyclohexanone could be repeated for six times
without significant decrease in enantioselectivities, and the
reaction yields were slightly decreased with the increase of
recycling times (Table 3).
the good yields and excellent enantioselectivities. The multi-
tudinous advantages of R-aminoxylation in RTILs, such as easy
recycling of solvents and chiral organocatalyst, high yields,
excellent enantioselectivities, short reaction times, and broad
substrate scope, make this synthetic method practical for organic
synthesis and suitable for potential industrial applications in the
future. On the basis of the present investigation, we are now
carrying out the research on the applications of ionic liquids
into other polar organocatalyst-mediated asymmetric reactions
with high enantioselectivities.
Experimental Section
General Procedure of L-Proline Catalyzed Direct Asymmetric
R-Aminoxylation of Aldehydes in Ionic Liquids. The mixture of
aldehyde (1.8 mmol), nitrosobenzene (96.5 mg, 0.9 mmol), and
L-proline (catalytic amount) in ionic liquid (1 mL) was stirred at
room temperature for the time indicated in Tables 1-3. After the
aminoxylation reaction was completed, the reaction mixture was
extracted with ethyl ether (10 mL × 4). To the combined ether
layer was added the solution of sodium borohydride (171 mg, 4.5
mmol) in ethanol (10 mL). The reaction mixture was stirred for 10
min at room temperature. Then, the reaction was quenched with
water (10 mL), and the resulting mixture was extracted with ethyl
acetate (5 mL × 3). The combined organic extracts were dried over
anhydrous magnesium sulfate and concentrated in vacuo after
filtration. Purification by column chromatography (silica gel, ethyl
acetate-petroleum ether as eluant) gave (2R)-2-aminoxy alcohol
2a-f in good to excellent yield.
In conclusion, we found that both aldehydes and ketones
could undergo direct asymmetric R-aminoxylation reaction
smoothly in RTILs, giving the desired (2R)-2-aminoxy alcohols
2a-f or ketones 1g-i in moderate to excellent yields. Compared
with that in common solvents, the yields of the direct R-ami-
noxylation of both aldehydes and ketones are improved sig-
nificantly in RTILs. At the same time, the direct R-aminoxy-
lation of aldehydes and ketones keeps excellent enantioselectivities
(95 f 99%) in various RTILs. It was also found that the direct
aminoxylation of ketones was accelerated greatly in RTILs.
Moreover, the ionic liquid containing L-proline could be
recovered easily and quantitatively after the direct R-aminoxy-
lation of aldehydes and ketones. The recovered ionic liquid
immobilizing L-proline could be reused for six cycles, keeping
8322 J. Org. Chem., Vol. 71, No. 21, 2006

General Procedure of Asymmetric R-Aminoxylation of Ke-
tones in Ionic Liquids. The mixture of ketone (2.7 mmol),
nitrosobenzene (96.5 mg, 0.9 mmol), and L-proline (catalytic
amount) in ionic liquid (1 mL) was stirred at room temperature for
the time indicated in (Tables 1-3). After the aminoxylation reaction
was completed, the reaction mixture was extracted with ethyl ether
(10 mL × 4). Then, the combined organic extracts were concen-
trated in vacuo to give crude product, which was purified by column
chromatography (silica gel, ethyl acetate-petrolium ether as eluant)
to afford (2R)-2-aminoxy ketone 1g-i in moderate to good yield.
Acknowledgment. We gratefully acknowledge the National
Natural Science Foundation of China for its financial support
of the Project 20332050 and Project 20572042.
Supporting Information Available: Experimental data, 1H
NMR, MS, and chiral HPLC spectra of 2a-f and 1g-i. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO061507G
J. Org. Chem, Vol. 71, No. 21, 2006 8323