Enantioselective organocatalysis in ionic liquids: Addition of aliphatic aldehydes and ketones to diethyl azodicarboxylate

Article abstract of DOI:10.1002/ejoc.200500481

The enantioselective addition of aldehydes to diethyl azodicarboxylate in ionic liquids in the presence of chiral organocatalysts has been investigated. Of seven different organocatalysts tested, L-proline and L-thiazoline-2- carboxylic acid gave the high

Full text of DOI:10.1002/ejoc.200500481

FULL PAPER
Enantioselective Organocatalysis in Ionic Liquids: Addition of Aliphatic
Aldehydes and Ketones to Diethyl Azodicarboxylate
[a]
[b]
[b]
[c]
ˇ
Peter Kotrusz, Sara Alemayehu, Stefan Toma,* Hans-Günther Schmalz, and
Andreas Adler[c]
Keywords: Organocatalysis / Ionic liquids / Proline / Asymmetric catalysis / Addition reactions
The enantioselective addition of aldehydes to diethyl azo-
dicarboxylate in ionic liquids in the presence of chiral
organocatalysts has been investigated. Of seven different
organocatalysts tested, L-proline and L-thiazoline-2-carbox-
ylic acid gave the highest enantioselectivities (up to 94% ee).
The best results were obtained by using [bmim]PF6 and
[hmim]BF4 as ionic liquids. The scope of the methodology
was probed by using various aldehydes and ketones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The catalysis of asymmetric reactions by small organic
molecules, so-called organocatalysts, has received a tremen-
dous amount of interest in recent years.[1–5] Besides asym-
metric aldol-type reactions, which represent the earliest and
most prominent examples, many other transformations in-
volving enamine intermediates are suitable for organocatal-
ysis, for example, the Michael addition of aldehydes or
ketones to β-nitrostyrenes.[6–9]
Recently, it was shown that the enantioselective addition
of aldehydes[10,11] or ketones[12,13] to dialkyl azodicarboxyl-
ates such as DEAD (2) can be performed in the presence
of chiral organocatalysts (Scheme 1). Reactions were most
frequently carried out at room temperature in acetonitrile
in the presence of 10–20 mol-% of l-proline as catalyst. By
switching to dichloromethane as the solvent, rather long re-
action times (up to several days) could be dramatically
shortened. This way, high yields of products (80–96%) were
obtained within a few hours by using as little as 2 mol-%
of the catalyst. To avoid racemization, enantioselectivities
were determined after reduction of the aldehyde/ketone
functionality of the primary reaction products and subse-
quent cyclization to the corresponding oxazolidinones. In
many cases, the oxazolidinones were prepared in Ն99% ee.
Scheme 1.
As an extension of this methodology, Bräse and co-
workers[14] described the amination of α,α-disubstituted al-
dehydes while Barbas and co-workers[15] achieved an l-pro-
line-catalyzed one-pot transformation with the initially
formed α-aminated aldehydes being directly trapped in an
aldol reaction with acetone. Instead of an azodicarboxylate,
nitrosobenzene was identified as a suitable electrophile
in related organocatalytic α-oxyaminations of alde-
hydes.[12,16–18] Again, l-proline was found to be a very good
catalyst and high yields and enantioselectivities were ob-
tained by using acetonitrile, DMSO or chloroform as the
solvent.
In recent years, ionic liquids have emerged as frequently
used “green” solvents for many organic reactions including
transition-metal-catalyzed reactions.[19–25] In organocatal-
ysis, ionic liquids have been used for the quinidinium bro-
mide catalyzed Michael addition of dimethyl malonate to
chalcone.[26] Recently, we[27] and (independently) Loh et
al.[28] found that ionic liquids are excellent solvents for l-
[a] SYNKOLA, s.r.o.,
84215 Bratislava, Slovakia
[b] Faculty of Natural Sciences, Comenius University Bratislava,
84215 Bratislava, Slovakia
Fax: +42-11-2-60296-690,
E-mail: toma@fns.uniba.sk
[c] Institut für Organische Chemie, Universität zu Köln,
50939 Köln, Germany
4904
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500481
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Enantioselective Organocatalysis in Ionic Liquids
FULL PAPER
proline-catalyzed aldol reactions. In addition, we have dem- strate 1a (1.5 equiv.) and the catalyst (10%). The almost
onstrated that the combination of l-proline and an ionic quantitative yields (Ն98%) match those previously reported
liquid also represents an excellent medium for the enantio- for the same reaction system in acetonitrile[12] and thus
selective Michael addition of aldehydes and ketones to β- demonstrate the competitiveness of the ionic liquid.
nitrostyrenes.[29] Following from this, the aim of the work
The data in Table 1 also show that reactions involving
described herein was to further explore and evaluate the ketones as substrates gave less satisfactory results. Only in
applicability of ionic liquids in organocatalysis. As a spe- the case of cyclobutanone (1i) was the mono-aminated
cific reaction system, the enantioselective addition of alde- product isolated in 43% yield. On the other hand, cyclo-
hydes and ketones to DEAD was studied (Scheme 1).
hexanone (1k) afforded a significant amount of an insepa-
rable mixture of the mono- and bis-aminated products 3k–1
and 3k–2 (38 and 21%, respectively). This result seemingly
contrasts the work of Jørgensen and co-workers[12] who re-
ported high yields and enantioselectivities for related reac-
tions in traditional solvents (using 1.5 equiv. of the sub-
strate and up to 20 mol-% of l-proline) without mentioning
the formation of any bis-aminated product. We therefore
performed an experiment with an increased amount
(1.5 equiv.) of cyclohexanone and obtained the mono-amin-
ated product in a respectable yield (58%) along with 11%
of the bis-addition product (Table 1, entry 13). In the reac-
tion with cycloheptanone we were able to isolate only 11%
of a mixture of the mono- and bis-aminated products even
after a prolonged reaction time of 24 h. Note that the
mono- and bis-aminated products could not be separated
by column chromatography and the ratios of isomers was
Results and Discussion
We started our investigation by examining the l-proline-
catalyzed addition of different aldehydes and ketones (Fig-
ure 1) to DEAD using [bmim]PF6 as a (common) ionic li-
quid. All reactions were performed at room temperature on
a 1 mmol scale in 1 mL of ionic liquid. Decoloration of the
reaction mixture indicated complete consumption of
DEAD. The results of this first set of experiments are given
in Table 1. Not unexpectedly, reaction rates were found to
correlate with the structures of the carbonyl derivatives. In
the presence of 5 mol-% of l-proline, the reaction of 3-
methylbutanal (1a) was complete within 1 hour while signif-
icantly longer reaction times (Ն18 h) were necessary for the
reactions of the sterically hindered aldehyde 1d and the
various ketones.
1
determined from the H NMR spectra of the crude mix-
tures. To our surprise the reactions with cyclopentanone (1j)
and 1-tetralone (1m) failed in spite of the fact that experi-
ments were performed several times with prolonged reac-
tion times or at a higher temperature (40 °C).
As mentioned above, the complete consumption of
DEAD was indicated by the decoloration of the reaction
mixtures at the end of the reaction. The rather low product
yields observed in several cases (Table 1) can nevertheless
be explained by a competitive reduction of the azo group
in DEAD. In fact, during the slow reactions the corre-
sponding hydrazo derivative, that is, EtOOC–NH–NH–CO-
OEt, was isolated. It is well known that the 2-C–H hydro-
gen atom of the 1,3-dialkylimidazolium ionic liquid is acidic
and we assumed that DEAD could oxidize the imidazolium
moiety of the ionic liquid by formation of the respective
dimer in a way similar to that described for the oxidation
by DEAD of thiols to disulfides.[30] To check this possibility
we dissolved DEAD in [bmim]PF6 and left it standing (in
darkness) at room temperature. After 48 hours the color of
the solution had changed from red to yellow, which indi-
cates reduction of diethyl azodicarboxylate to diethyl
hydrazodicarboxylate.
Having so far demonstrated that in general it is possible
to perform the proline-catalyzed addition of aldehydes to
DEAD in an ionic liquid, our next aim was to study the
enantioselectivity of such reactions and particularly the ef-
Figure 1. Carbonyl substrates used in this study.
It is remarkable that very high product yields were ob- fects of solvent and catalyst. Initial attempts to determine
tained with the simple aldehydes 1a, 1b and 1e despite the the enantiomeric purity of the product derived from 1a by
fact that only a slight excess (1.1 equiv.) of these substrates means of 1H NMR spectroscopy in the presence of a chiral
and only 5 mol-% of the catalyst were employed. For com- shift reagent did not lead to reliable results due to relatively
parison purposes, two additional experiments (Table 1, en- rapid racemization.[10,11] We therefore decided to convert
tries 2 and 3) were performed with larger amounts of sub- the sensitive primary reaction products (aldehydes of type
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P. Kotrusz, S. Alemayehu, S. Toma, H.-G. Schmalz, A. Adler
FULL PAPER
Table 1. Results of the l-proline-catalyzed addition of aliphatic aldehydes and ketones to DEAD in [bmim]PF6 (see Scheme 1).[a]
[a] Unless otherwise stated, reactions were performed at room temperature using 1.1 equiv. of the carbonyl substrate (see Figure 1),
1.0 equiv. of DEAD and 5 mol-% of l-proline; yield of isolated product 3. [b] 1.5 Equiv. of 1a and 5 mol-% of l-proline were used.
[c] 1.5 Equiv. of 1a and 10 mol-% of l-proline were used. [d] An inseparable mixture of regioisomers (85:15) was obtained. [e] Bis-aminated
product. [f] 1.5 Equiv. of cyclohexanone was used. [g] An inseparable mixture of mono- and bis-products was obtained.
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Enantioselective Organocatalysis in Ionic Liquids
FULL PAPER
3) into configurationally stable N-(ethoxycarbonylamino)- (formerly called ECOENGTM 500), CYPHOSIL 101 and
oxazolidinone derivatives 4[10,12] by reduction with NaBH4 [bmim]C8H17SO4, gave unsatisfactory results. Whilst the
and subsequent treatment with aqueous NaOH. A series yield and enantioselectivity observed for the reaction in
of experiments was performed by using aldehyde 1a as the [bmim]BF4 are quite pleasing, it should be mentioned that
substrate (Scheme 2) and by keeping the reaction time con- the values obtained are lower than those reported for the
stant (65 min). The results are summarized in Table 2.
reaction of compound 1a in acetonitrile by List,[11] who,
however, used a larger excess of substrate and twice the
amount (10 mol-%) of l-proline.
As part of this study, we intended to probe the relative
efficacy of several different organocatalysts (C1–C7; see
Figure 2) in the synthesis of oxazolidinones of type 4 in an
ionic liquid. For reasons of comparison, we used the same
reaction system as that used to obtain product 4a
(Scheme 2). The results are summarized in Table 3.
Scheme 2.
Table 2. l-Proline-catalyzed addition of 1a to DEAD and subse-
quent conversion of the product to 4a using the conditions given
in Scheme 2.
Entry
Ionic liquid
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]PF6
[hmim]BF4
[hmim]PF6
[bbim]PF6
85
76[c]
51[d]
41[e]
68
88
44
65
48
46
84
84
79
72
79
36
81
83
70
17
11
n.d.
Figure 2. Organocatalysts used in this study.
Table 3. Addition of 1a to DEAD in [bmim]BF4 under the condi-
tions given in Scheme 3. Relative performance of different organo-
catalysts.
9
[C10mim]BF4
[bmim]C8H17SO4
AMMOENG 100[f]
CYPHOSIL 101
10
11
12
Yield [%] ee
Entry Catalyst Time, temperature
44
[a]
[%][b]
45[g]
1
2
3
4
5
6
7
8
9
C1
C1
C2
C2
C2
C3
C3
C4
C4
65 min, room temp.
65 min, room temp.
360 min, room temp.
65 min, room temp.
380 min, room temp.
480 min, room temp.
330 min, 60–70 °C
420 min, room temp.
280 min, room temp. +
300 min, 70 °C
85
89
8
45
27
17
65
Ͻ4
36
84
[a] Reactions were performed at room temperature using 1.1 equiv.
of 1a, 1.0 equiv. of DEAD and 5 mol-% of l-proline; yield of iso-
lated product (after column chromatography). [b] The enantiomeric
excess was determined by GC using a chiral stationary phase [hep-
takis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)-β-cyclodextrin
on silica gel]. [c] First re-use of the catalytic system. [d] Second re-
use of the catalytic system. [e] Third re-use of the catalytic system.
[f] From Solvent Innovation GmbH, Köln, formerly called ECO-
ENG 500. [g] The product was very difficult to isolate in this case.
85[c]
72
73[c]
94
92
58
n.d.
33[d]
10
11
12
C5
C6
C7
65 min, room temp.
50 min, room temp.
330 min, room temp.
46
62
22
Յ2
Յ2
36
As Table 2 shows, [bmim]BF4 proved to be the best ionic
liquid investigated with respect to both yield (85%) and
enantioselectivity (84% ee). Re-use of the catalytic system
(ionic liquid and catalyst after extraction with diethyl ether)
was possible, however, the yield dropped considerably poss-
ibly due to partial loss of the organocatalyst during the ex-
traction. The enantioselectivity remained high in the re-
peated experiments (Table 2, entries 2–4). Interestingly, the
[a] Unless otherwise stated, reactions were performed with
1.1 equiv. of substrate (1a), 1 equiv. of DEAD and 5 mol-% of or-
ganocatalyst at room temperature; yield of isolated product (4a)
after column chromatography. [b] The enantiomeric excess was de-
termined by GC using a chiral stationary phase [heptakis(6-O-tert-
butyldimethylsilyl-2,3-di-O-methyl)-β-cyclodextrin on silica gel].
[c] Reactions were performed with 30 mol-% of catalyst. [d] After
so-called “even greener” ionic liquids, AMMOENG 100 200 min, an additional 5 mol-% of catalyst was added.
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P. Kotrusz, S. Alemayehu, S. Toma, H.-G. Schmalz, A. Adler
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As the data in Table 3 show, l-proline (C1) is the best of
the catalysts tested with respect to turnover rate (85% yield
in 65 min) and it also gave a good enantioselectivity (84%
ee). trans-4-Hydroxy-l-proline (C2) and l-thiazolidine-2-
carboxylic acid (C3) afforded products with higher enantio-
selectivities (94 and 92% ee, respectively), however, the reac-
tions with these catalysts were very slow and only low yields
were obtained even after prolonged reaction times. Increas-
ing the amount of catalyst from 5 to 30 mol-% had only a
minor effect in the case of l-proline (Table 3, entry 2), how-
ever, it led to a significant increase in yield (from 8 to 45%)
in the case of catalyst C2 (entries 3 and 4). An attempt to
use serine (C4) as the catalyst, which may form octamers
with an inert chiral cavity,[31] was not successful; only traces
of the product were formed with 5 mol-% of catalyst C4 at
room temperature and even heating the mixture to 60–
70 °C for several hours in the presence of 10 mol-% of cata-
lyst only gave a 36% yield of product and a rather low
enantioselectivity (33% ee). The other catalysts (C5–C7)
also gave low yields and enantioselectivities. Note that use
Scheme 3.
Table 4. l-Proline-catalyzed addition of various aldehydes to DEAD in [bmim]BF4 under the conditions indicated in Scheme 3.
[a] Reactions were performed at room temperature using 1.1 mmol of aldehyde, 1 mmol of DEAD in 1 mL of [bmim]BF4 in the presence
of 5 mol-% of l-proline; yield of isolated product 4 after column chromatography. [b] Determined by GC using a chiral stationary phase
[heptakis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)-β-cyclodextrin on silica gel]. [c] ee determined by HPLC.
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Enantioselective Organocatalysis in Ionic Liquids
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The crude product 3 was purified by column chromatography on
SiO2 (Table 1).
of C7 as the catalyst afforded the opposite enantiomer to
that obtained with the other catalysts; the bulky phenyl
group probably hinders the approach of the enamine inter-
mediate to DEAD from the same side as the l-proline-de-
rived enamine. The formation of an excess of the opposite
enantiomer was proved by HPLC.
General Experimental Procedure for the Preparation of Compounds
4: The catalyst (5 mol-%) and the chosen substrate 1 (1.1 equiv.)
were added to the degassed ionic liquid (1 mL). After stirring the
resulting mixture for 15 min at room temp. DEAD (1 mmol, 40%
solution in toluene) was added and vigorous stirring was continued
for the time and at the temperature specified in the tables. The
product was isolated by extraction with several portions of diethyl
ether followed by solvent evaporation using a rotary evaporator.
To achieve the latter, the crude product 3 was dissolved in MeOH
(3 mL). The mixture was cooled to 3 °C and NaBH4 (1.1 equiv.)
was added. After stirring for 15 min at room temp., a 0.5 m solution
of NaOH was added and stirring was continued for 25 min before
water (7 mL) was added. The mixture was extracted with EtOAc
(3×5 mL) and the combined organic layers were dried with
Na2SO4. After evaporating the solvent in vacuo, the crude product
4 was purified by column chromatography on SiO2 with hexane/
EtOAc (4:1) or hexane/dichloromethane (2:1) as eluent.
Finally, to explore the scope of this methodology, we in-
vestigated the reactions of different aldehydes (Scheme 3)
under the conditions optimized for the model substrate 1c
(5 mol-% l-proline in [bmim]BF4). As the results summa-
rized in Table 4 indicate, good yields and enantioselectivit-
ies (up to 89% ee) were obtained for the small aliphatic
aldehydes 1a, 1b and 1c. The sterically crowded substrate
1e reacted much more slowly, but the enantioselectivity was
only slightly lower. With phenylacetaldehyde (1f) no conver-
sion was observed under the standard conditions (addition
of DEAD to a stirred solution of l-proline and the alde-
hyde). In contrast, when aldehyde 1f was added to a solu-
tion of l-proline and DEAD in the ionic liquid the addition
product 3f was formed, but due to the lability of this com-
pound it was immediately converted into the corresponding
oxazolidinone 4f. A reasonable yield of compound 4f was
obtained (43%), but the enantioselectivity was rather low.
N,NЈ-Bis(ethoxycarbonyl)-2-hydrazino-3-methylbutyraldehyde (3a):
1
Yield: 239 mg (92%); H NMR (300 MHz, CDCl3): δ = 9.76 (s, 1
H), 6.61 (br. s, 1 H), 4.42 (m, 1 H), 4.21 (q, J = 7.2 Hz, 2 H), 4.21
(q, J = 7.2 Hz, 2 H), 4.37–4.25 (m, 1 H), 1.28 (t, J = 7.2 Hz, 3 H),
1.27 (t, J = 7.2 Hz, 3 H), 1.15 (d, J = 4.5 Hz, 3 H), 1.07 (d, J =
4.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 199.9, 156.7,
72.4, 63.4, 62.4, 27.6, 20.2, 19.7, 14.6, 14.5 ppm. C11H20N2O5
(260,29): calcd. C 50.76, H 7.74, N 10.76; found C 49.85, H 7.90,
N 10.59. Colourless oil, RF = 0.05 (SiO2, Hex/EtOAc = 9:1).
Conclusions
N,NЈ-Bis(ethoxycarbonyl)-2-hydrazinopropionaldehyde
(3b):[10]
The aim of this study was to probe the potential of ionic
liquids as solvents for organocatalysis. By using the ad-
dition of aldehydes (and ketones) to DEAD as an example,
the combination of [bmim]BF4 as an ionic liquid and l-
proline (5 mol-%) as an organocatalyst was identified as a
suitable reaction system. While the reactions of ketones did
not produce useful results, the reactions of various alde-
hydes afforded products in good chemical yields (up to
85%) and enantioselectivities (up to 89%). As shown in one
case, even higher yields and enantioselectivities can be ob-
tained if larger amounts of catalyst (10 mol-%) and alde-
hyde (1.5 equiv.) are employed. These results are compar-
able to those obtained under similar conditions in tradi-
tional solvents, however, for the transformation investi-
gated, the reaction rates seem to be even faster in ionic li-
quids. Therefore, it can be concluded that ionic liquids are,
in principle, very well suited to such reactions. Owing to the
special qualities of ionic liquids as “green” solvents, further
exploration of their potential application in other organ-
ocatalytic systems seems worthwhile.[32]
Yield: 232 mg (82%); 1H NMR (300 MHz, CDCl3): δ = 9.65 (br.
s, 1 H), 6.57 (br. s, 1 H), 4.76 (br. s, 1 H), 4.21–4.11 (m, 4 H), 1.31
(d, J = 7.5 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2 Hz,
3 H) ppm. Colourless oil, RF = 0.02 (SiO2, Hex/EtOAc = 9:1).
N,NЈ-Bis(ethoxycarbonyl)-2-hydrazinobutyraldehyde (3c):[10] Yield:
1
190 mg (52%); H NMR (300 MHz, CDCl3): δ = 9.63 (br. s, 1 H),
6.69 (br. s, 1 H), 4.46 (m, 1 H), 4.21 (q, 2 H), 4.16 (q, 2 H), 1.92
(m, 1 H), 1.69 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.06 (t, J =
7.2 Hz, 3 H) ppm. Colourless oil, RF = 0.07 (SiO2, Hex/EtOAc =
9:1).
N,NЈ-Bis(ethoxycarbonyl)-2-hydrazino-3,3-dimethylbutyraldehyde
1
(3d): Yield: 77 mg (28%); H NMR (300 MHz, CDCl3): δ = 9.71
(s, 1 H), 6.52 (br. s, 1 H), 4.56 (m, 1 H), 4.19–4.08 (m, 4 H), 1.59
(t, 3 H), 1.50 (t, 3 H), 1.39 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 202.87, 156.37, 151.42, 71.80, 62.37, 59.32, 44.18,
29.50, 14.04, 13.93 ppm. C12H22N2O5 (274.32): calcd. C 52.54, H
8.08, N 10.21; found C 52.60, H 8.12, N 10.27. Colourless oil, RF
= 0.06 (SiO2, Hex/EtOAc = 9:1).
2-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-3-phenylpropionaldehyde
1
(3e): Yield: 256 mg (83%); H NMR (300 MHz, CDCl3): δ = 8.97
(d, 1 H), 8.92 (br. s, 1 H), 7.24–7.14 (m, 3 H), 6.97 (m, 2 H), 5.42
(m, 1 H), 4.14 (m, 4 H), 3.22 (t, 2 H), 1.66 (m, 6 H) ppm.
C15H20N2O5 (308.34): calcd. C 58.43, H 6.54, N 9.09; found C
58.35, H 6.58, N 9.15. Colourless oil, RF = 0.12 (SiO2, Hex/EtOAc
= 9:1).
Experimental Section
General Experimental Procedure for the Preparation of Compounds
3: The catalyst (5 mol-%) and the chosen substrate 1 (1.1 equiv.)
were added to the degassed ionic liquid (1 mL). After stirring the
resulting mixture for 15 min at room temp. DEAD (1 mmol, 40%
solution in toluene) was added and vigorous stirring was continued
for the time and at the temperature specified in the tables. The
product was isolated by extraction with several portions of diethyl
ether followed by solvent evaporation using a rotary evaporator.
2-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-3-pentanone (3g):[12] Yield:
36 mg (14%); H NMR (300 MHz, CDCl3): δ = 6.66 (br. s, 1 H),
4.92 (br. s, 1 H), 4.25–4.14 (m, 4 H), 2.54–2.48 (m, 2 H), 1.42 (d,
J = 7.5 Hz, 3 H), 1.30–1.23 (m, 6 H), 1.07 (t, J = 7.5 Hz, 3 H) ppm.
RF = 0.32 (SiO2, CH2Cl2/EtOAc = 4:1).
1
3-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-4-methyl-2-pentanone (3h-
1
1):[12] Yield: 201 mg (8% total for a mixture of 3h-1 and 3h-2); H
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NMR (300 MHz, CDCl3): δ = 6.61 (br. s, 1 H), 4.59 (br. s, 1 H),
4.25–4.14 (m, 4 H), 2.38–2.28 (m, 1 H), 2.29 (s, 3 H), 1.29–1.24 (m,
6 H), 1.02–0.93 (m, 6 H) ppm. RF = 0.41 (SiO2, CH2Cl2/EtOAc =
4:1).
C 44.68, H 6.43, N 14.89; found C 44.71, H 6.45, N 14.92. Pale
yellow oil, RF = 0.35 (SiO2, CH2Cl2/Et2O = 4:1).
3-(Ethoxycarbonylamino)-4-ethyl-2-oxazolidinone (4c):[10] Yield:
1
127 mg (63%); H NMR (300 MHz, CDCl3): δ = 6.50 (br. s, 1 H),
4.91 (m, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.00 (m, 2 H), 1.85 (m, 1
H), 1.59 (m, 1 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.76, 155.60, 67.31,
62.64, 57.82, 24.52, 14.53, 8.62 ppm. C8H14N2O4 (202.21): calcd. C
47.52, H 6.98, N 13.85; found C 47.58, H 6.71, N 13.82. Pale yellow
oil, RF = 0.56 (SiO2, CH2Cl2/Et2O = 4:1).
1-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-4-methyl-2-pentanone (3h-
2):[12] 1H NMR (300 MHz, CDCl3): δ = 6.89 (br. s, 1 H), 4.25–4.14
(m, 6 H), 2.61 (m, 2 H), 2.19–2.11 (m, 1 H), 1.29–1.24 (m, 6 H),
1.02–0.93 (m, 6 H) ppm. RF = 0.41 (SiO2, CH2Cl2/EtOAc = 4:1).
2-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-1-cyclobutanone (3i): Yield:
1
105 mg (43%); H NMR (300 MHz, CDCl3): δ = 6.32 (br. s, 1 H),
4-tert-Butyl-3-(ethoxycarbonylamino)-2-oxazolidinone (4d):[10]
6.07 (m, 1 H), 4.12 (m, 4 H), 2.71 (m, 2 H), 2.01 (m, 2 H), 1.59 (t,
3 H), 1.46 (t, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 209.68,
155.19, 154.20, 62.42, 59.39, 56.82, 41.44, 23.75, 14.49, 14.03 ppm.
C10H16N2O5 (244.25): calcd. C 49.18, H 6.60, N 11.47; found C
49.23, H 6.65, N 11.50. Colourless wax, RF = 0.56 (SiO2, CH2Cl2/
EtOAc = 4:1).
1
Yield: 78 mg (34%); H NMR (300 MHz, CDCl3): δ = 6.61 (br. s,
1 H), 4.41 (t, J = 8.7 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.12 (t,
J = 8.4 Hz, 1 H), 3.84 (m, 1 H,), 1.29 (t, J = 7.2 Hz, 3 H), 0.97 (s,
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.14, 155.30, 64.76,
62.68, 33.58, 25.68, 14.58 ppm. C10H18N2O4 (230.27): calcd. C
52.16, H 7.88, N 12.17; found C 52.20, H 7.90, N 12.21. Pale yellow
oil, RF = 0.50 (SiO2, CH2Cl2/Et2O = 4:1).
2-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-1-cyclohexanone (3k-1):[12]
1
Yield: 208 mg (as a mixture of 38% of 3k-1 and 21% of 3k-2); H
4-Benzyl-3-(ethoxycarbonylamino)-2-oxazolidinone (4e):[10] Yield:
NMR (300 MHz, CDCl3): δ = 6.68 (br. s, 1 H), 4.90 (m, 1 H),
4.23–4.13 (m, 4 H), 2.52–2.48 (m, 1 H), 2.42–2.30 (m, 2 H), 2.13–
2.05 (m, 1 H), 2.00–1.97 (m, 1 H), 1.87–1.71 (m, 2 H), 1.65–1.55
(m, 1 H), 1.29–1.24 (m, 6 H) ppm. Colourless wax, RF = 0.30 (SiO2,
CH2Cl2/EtOAc = 4:1).
1
113 mg (43%); H NMR (300 MHz, CDCl3): δ = 7.36–7.24 (m, 3
H), 7.17–7.15 (m, 2 H), 6.54 (br. s, 1 H), 4.32 (m, 2 H), 4.23 (q, J
= 6.9 Hz, 2 H), 4.07 (m, 1 H), 3.18 (dd, J = 13.8, J = 4.2 Hz, 1 H),
2.81 (dd, J = 13.8, J = 8.7 Hz, 1 H), 1.29 (t, J = 6.9 Hz, 3 H) ppm.
C13H16N2O4 (264.28): calcd. C 59.08, H 6.10, N 10.60; found C
59.12, H 6.08, N 10.67. Pale yellow oil, RF = 0.45 (SiO2, CH2Cl2/
Et2O = 4:1).
2,6-Bis[N,NЈ-bis(ethoxycarbonyl)hydrazino]-1-cyclohexanone (3k-
2):[12] 1H NMR (300 MHz, CDCl3): δ = 6.93 (br. s, 2 H), 4.66–4.60
(m, 2 H), 4.17–4.11 (m, 8 H), 2.76 (m, 2 H), 2.14 (m, 4 H), 1.61 (t,
12 H) ppm. Colourless wax, RF = 0.30 (SiO2, CH2Cl2/EtOAc =
4:1).
3-(Ethoxycarbonylamino)-4-phenyl-2-oxazolidinone (4f): Yield:
1
105 mg (42%); H NMR (300 MHz, CDCl3): δ = 7.35–7.29 (m, 5
H), 6.26 (br. s, 1 H), 4.12 (m, 3 H), 3.81 (dd, J = 11.7, J = 4.2 Hz,
1 H), 3.68 (dd, J = 11.7, J = 8.1 Hz, 1 H), 1.23 (t, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 158.19, 138.85, 128.80, 128.14,
127.97, 66.25, 64.51, 61.83 ppm. C12H14N2O4 (250.26): calcd. C
57.59, H 5.64, N 11.19; found C 57.71, H 5.69, N 11.10. Pale yellow
oil, RF = 0.49 (SiO2, CH2Cl2/Et2O = 4:1).
Note: An inseparable mixture of mono- and bis-aminated products
was isolated but the two products could be distinguished by NMR
spectroscopy.
2-[N,NЈ-Bis(ethoxycarbonyl)hydrazino]-1-cycloheptanone (3l-1):
Yield: 38 mg (8% total for a mixture of 3l-1 and 3l-2); 1H NMR
(300 MHz, CDCl3): δ = 6.75 (br. s, 1 H), 4.99 (m, 1 H), 4.23–4.12
(m, 4 H), 2.66–2.59 (m, 2 H), 2.43–2.32 (m, 2 H), 2.21 (m, 1 H),
1.98–1.92 (m, 2 H), 1.75–1.65 (m, 3 H), 1.29–1.23 (m, 6 H) ppm.
Colourless oil, RF = 0.39 (SiO2, CH2Cl2/EtOAc = 4:1).
Acknowledgments
We are grateful to Solvent Innovation Comp., Köln, for a gift of
AMMOENGTM 100 ionic liquid and to Cytec Canada, Niagara
Falls for a gift of CYPHOSIL 101 ionic liquid. This work was
supported by the Slovak Grant Agency VEGA (grant No. 1/0072/
03). The authors are also grateful to an anonymous referee whose
comments helped us to improve the quality of the paper.
2,7-Bis(N,NЈ-bis(ethoxycarbonyl)hydrazino]-1-cycloheptanone (3l-2):
1H NMR (300 MHz, CDCl3): δ = 6.90 (br. s, 2 H), 5.11 (m, 2
H), 4.14 (m, 8 H), 2.03–1.93 (m, 4 H), 1.68–1.54 (m, 16 H) ppm.
Colourless oil, RF = 0.39 (SiO2, CH2Cl2/EtOAc = 4:1).
Note: An inseparable mixture of mono- and bis-aminated products
was isolated but the two products could be distinguished by NMR
spectroscopy.
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1
181 mg (85%); H NMR (300 MHz, CDCl3): δ = 6.56 (br. s, 1 H),
4.39 (t, J = 8.7 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.08 (t, J =
8.4 Hz, 1 H), 3.97 (m, 1 H), 2.00–2.11 (m, 1 H), 1.29 (t, J = 7.2 Hz,
3 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.94 (d, J = 7.2 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 158.25, 155.48, 64.21, 62.69, 61.02,
61.02, 28.68, 18.01, 16.04, 14.55 ppm. C9H16N2O4 (216.24): calcd.
C 49.99, H 7.46, N 12.95; found C 49.96, H 7.42, N 12.98. Colour-
less oil, RF = 0.48 (SiO2, CH2Cl2/EtOAc = 4:1).
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3-(Ethoxycarbonylamino)-4-methyl-2-oxazolidinone (4b):[10] Yield:
1
118 mg (63%); H NMR (300 MHz, CDCl3): δ = 6.57 (br. s, 1 H),
4.51 (t, J = 8.4 Hz, 1 H), 4.23 (q, J = 6.9 Hz, 2 H), 4.13 (m, 1 H),
3.91 (t, J = 8.4 Hz, 1 H), 1.32 (d, J = 6 Hz, 3 H), 1.30 (t, J =
6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.32, 155.43,
68.81, 62.52, 52.87, 16.89, 14.36 ppm. C7H12N2O4 (188.18): calcd.
4910
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4904–4911

Enantioselective Organocatalysis in Ionic Liquids
FULL PAPER
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Received: June 29, 2005
Published Online: October 4, 2005
Eur. J. Org. Chem. 2005, 4904–4911
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4911