Michael additions of aldehydes and ketones to β-nitrostyrenes in an ionic liquid

Article abstract of DOI:10.1002/ejoc.200300648

Michael additions of different aldehydes and ketones to β-nitrostyrene and 2-(β-nitrovinyl)thiophene in 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF₆) were studied. β-Nitrostyrene was a better acceptor than 2-(β-nitrovinyl)thiophen

Full text of DOI:10.1002/ejoc.200300648

FULL PAPER
Michael Additions of Aldehydes and Ketones to β-Nitrostyrenes in an Ionic
Liquid
Peter Kotrusz,[a] Stefan Toma,*[b] Hans-Günther Schmalz,[c] and Andreas Adler[c]
Keywords: Ionic liquids / -Proline / Michael additions / β-Nitrostyrenes / Organocatalysis
Michael additions of different aldehydes and ketones to β-
nitrostyrene and 2-(β-nitrovinyl)thiophene in 1-butyl-3-
methylimidazolium hexafluorophosphate ([bmim]PF6) were
studied. β-Nitrostyrene was a better acceptor than 2-(β-nitro-
vinyl)thiophene, in terms of both reactivity and selectivity.
Aldehydes proved to be better donors than ketones, which
were themselves better than β-diketones. -proline proved to
be the best catalyst among seven organocatalysts tested.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
L
Introduction
Michael addition of dimethyl malonate to chalcone[27] and
addition of thiols to α,β-unsaturated ketones.[28] We[29] and,
simultaneously, Loh et al.[30] have found that ionic liquids
are also excellent solvents for proline-catalysed aldol reac-
tions. Following this line, the aim of the work described
here was to explore whether ionic liquids can also be used
as solvents for -proline-catalysed Michael additions to β-
nitrostyrenes.
The Michael addition is one of the most frequently used
CϪC bond-forming reactions in organic synthesis.[1Ϫ5]
Great progress has been achieved in the asymmetric version
of this reaction[6Ϫ8] and the asymmetric Michael addition
to nitroalkenes has also been described.[9] Among the most
frequently used catalysts in asymmetric Michael additions
are Cinchona alkaloids and their derivatives[10,11] as well
as BINOL-based heterobimetallic catalysts.[12] Asymmetric
reactions catalysed by small organocatalysts have become
very attractive in recent years,[13Ϫ17] and this type of cataly-
sis has also been used for Michael additions of aldehydes
and ketones to nitrostyrenes.[18Ϫ21] DMSO and chloroform
are the most frequently employed solvents in proline-cata-
lysed reactions, although methanol is also a suitable sol-
vent. This was recently shown by Enders in a thorough
study of the solvent effect on the course of -proline-cata-
lysed reactions.[22] Barbas III[18] has also used THF as the
solvent, but the yield with -proline was just 5% and (S)-2-
(morpholinomethyl)pyrrolidine had to be used as the cata-
lyst to achieve high yields. Reaction times of such reactions
are generally long (2Ϫ4 days) and the yields can reach up
to 85%. The best selectivities for such reactions were de-
scribed by Enders[21] who reached a diastereomeric ratio
(dr) of approx. 80:20 and ee values varying from 25 to 78%.
In recent years, ionic liquids have emerged as frequently
used ‘‘green’’ solvents for many organic reactions including
transition metal-catalysed reactions.[22Ϫ26] Ionic liquids
have also been used for quinidinium bromide-catalysed
Results and Discussion
We started our investigation with an examination of the
catalytic efficacy of several chiral amino acids or com-
pounds derived from them. The reaction of β-nitrostyrene
(1a) with isobutyraldehyde (2b) (Scheme 1) was used to test
the catalytic activity of seven different small organic mol-
ecules (CAT1 Ϫ CAT7) (Figure 1). All reactions were per-
formed in 1-butyl-3-methylimidazolium hexafluorophos-
phate ([bmim]PF6) as the solvent in the presence of 5 mol %
of a catalyst.
The results given in Table 1 show that the best catalyst
proved to be simple -proline (CAT1). The second best was
2-(N-morpholinomethyl)pyrrolidine (CAT4). While most of
the other catalysts were more or less inactive, trans-4-
hydroxy--proline (CAT3) exhibited significant activity at
elevated temperatures (80 °C). The attempt to use free
CAT4 (without TfOH) was also promising, because 45%
yield of the product was isolated after 22 h at room tem-
perature, but all of the catalyst together with the product
was extracted into diethyl ether and no re-use of the cata-
lytic system was possible.
[a]
SYNKOLA Consortium,
842 15 Bratislava, Slovakia
[b]
Faculty of Natural Sciences, Comenius University Bratislava,
842 15 Bratislava, Slovakia
As mentioned above, there are several papers[18Ϫ21]
describing -proline-catalysed additions of aldehydes or ke-
[c]
Institut für Organische Chemie, Universität zu Köln,
50939 Köln, Germany
Eur. J. Org. Chem. 2004, 1577Ϫ1583
DOI: 10.1002/ejoc.200300648
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1577

P. Kotrusz, S. Toma, H.-G. Schmalz, A. Adler
FULL PAPER
Scheme 1
Table 1. Results of the catalysts screening
Entry
Catalyst
t (°C)/Time (h)
Yield (%)
dr (syn/anti)
(NMR)
1
2
3
4
5
6
7
8
9
CAT1
CAT2
CAT2
CAT3
CAT3
CAT4
CAT4[a]
CAT4[a]
CAT5
CAT6
CAT7
room temp./22
room temp./22
80/12
room temp./22
80/12
room temp./100
room temp./22
room temp./48
room temp./22
room temp. /22
room temp. /22
83
0
16
0
51
34
45
45
0
9:1
Ϫ
10:1
Ϫ
4:3
3:1
3:1
3:1
Ϫ
10
11
0
0
Ϫ
Ϫ
[a]
A naked CAT4 (not containing TfOH) was used in this experi-
ment. This catalyst is very soluble in diethyl ether so the IL/catalyst
system cannot be re-used.
The results given in Table 2 show that the reactions pro-
ceeded well using just 5 mol % of -proline as the catalyst,
and reasonable yields of the products were isolated after
24 h at room temperature. Obviously, there is a big differ-
ence from the published systems, where 15Ϫ20 mol % of
catalyst were necessary to obtain reasonable conversions
within 2Ϫ3 days. In comparison to simple propionic alde-
hyde (2a), aldehydes 2b؊2e give high yields, an exception
being 3,3-dimethylbutanal (2f) in which case no reaction
was observed even at higher temperature. This can be
rationalised by assuming that a bulky tert-butyl group pre-
cluded the formation or conversion of the suggested enam-
ine intermediate.[21] Two further experiments were per-
formed. In an ionic liquidϪchloroform system (Table 2, En-
try 7) the same results were achieved as in the pure ionic
liquid. The two phase ionic liquid/water system was less ef-
fective (Table 2, Entry 8).2
Interesting results were also observed for Michael ad-
ditions of cyclic ketones 2g؊2j. While the reaction of cyclo-
pentanone (2h) proceeded smoothly at room temperature,
which is in agreement with refs.[20,21], elevated temperatures
Figure 1. Structure of the catalysts
tones to β-nitrostyrenes, but usually either aldehydes[18] or were necessary to obtain good results with cyclobutanone
ketones[19,21] were studied, and therefore no direct compari- (2g), cyclohexanone (2i) and cycloheptanone (2j). We can-
son of their reactivity could be made. Moreover, other not explain this observation. One could only speculate
Michael donors such as β-diketones have never been tested. about subtle differences in the rate of formation and conver-
For this reason, we decided to examine the reactivity of a sion of the cyclic enamine intermediates.
broad range of Michael donors (Figure 2, 2aϪ2v) in the
Acyclic ketones 2k؊2n, especially those with bulky sub-
addition to β-nitrostyrene (1a) according to Scheme 2. stituents, proved to be less reactive than aldehydes and also
Again, [bmim]PF6 was used as the solvent in the presence less reactive than cyclic ketones, which is reflected by lower
of 5 mol % of -proline as a catalyst.
product yields even at elevated temperatures. It is worth
1578
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Eur. J. Org. Chem. 2004, 1577Ϫ1583

Michael Additions of Aldehydes and Ketones
FULL PAPER
Table 2. Results of Michael additions to β-nitrostyrene 1a
Entry
Reagent
t (°C)/Time (h)
Yield (%)
dr (syn/anti)
(NMR)
1
2
3
4
5
6
7
8
9
2a
2b
2b
2b
2c
2d
2d
2d
2e
2f
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./12
room temp./12
room temp./22
room temp./24
80/24
room temp./36
70/12
room temp./14
room temp./36
80/14
room temp./36
70/14
room temp./22
80 /22
room temp./22
80/22
room temp./22
80/22
room temp./22
80/22
room temp./14
room temp./14
80/22
room temp./12
80/22
room temp./14
room temp./14
room temp./14
room temp./14
room temp./36
80/48
58
83
70[a]
61[b]
89
93
90[c]
79[d]
64
0
0
0
53
69
4
87
0
67
35
77
0
23
0
5
0
25
45
9
3:1
9:1
6:1
5:1
6:1
5:1
5:1
5:1
8:1
Ϫ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
2f
Ϫ
Ϫ
2g
2g
2h
2i
4:3
3:2
n.d.
5:1
Ϫ
6:1
n.d.
n.d.
Ϫ
n.d.
Ϫ
n.d.
Ϫ
2i
2j
2j
2k
2k
2l
2l
2m
2m
2n
2n
2o
2p
2p
2q
2q
2r
2s
2t
1:1
Ϫ
Ϫ
38
17
51
55
80
81
41
0
Ϫ
3:2
3:2
Ϫ
Ϫ
3:2
12:1
Ϫ
2u
2v
2v
0
Ϫ
[a]
[b]
1st re-use of the IL Ϫ -proline system. 2nd re-use of the IL
[c]
Ϫ -proline system.
CHCl3 (1:1). Reaction was performed in [bmim]PF6: H2O (1:1)
two phase system.
Reaction was performed in [bmim]PF6:
Figure 2. Structure of the reagents
[d]
Scheme 2
noting that the reactions are clean and no side-products the assumption that they are enolised and their enols are
were detected. The low yields of the product can be raised stabilised by strong intramolecular hydrogen bonding. This
either by prolonging the reaction time or by performing the precludes the formation of the enamine which was sug-
reaction at higher temperature (see below).
gested as an intermediate[21] in -proline-catalysed reac-
It is interesting to compare the results achieved with dif- tions. This could explain the observed reactivity order 2o Ͼ
ferent β-diketones (2oϪ2r, 2u, 2v). Among the acyclic β- 2q Ͼ 2p. In the case of the cyclic β-diketones 2r, 2u, 2v,
diketones, acetylacetone (2o) gave rise to the highest yield. accordingly, a very good yield was achieved with indane-
The lower reactivity of β-diketones may be rationalised by 1,3-dione (2r) which is ‘‘unhindered’’ because its enol form
Eur. J. Org. Chem. 2004, 1577Ϫ1583
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P. Kotrusz, S. Toma, H.-G. Schmalz, A. Adler
FULL PAPER
cannot be stabilised by intramolecular hydrogen bonding.
In contrast, 2-acetylcyclohexan-1-one (2v) did not react
even at elevated temperatures, possibly because its geometry
allows the formation of a hydrogen bond-stabilised enol.
This assumption is also supported by the fact that high
yields of the products resulted from the reactions of malon-
odinitrile (2s) and methyl cyanoacetate (2t), neither of
which can form hydrogen bond-stabilised enolates. The
structures of the reaction products formed by addition to
1a and 1b are given in Figure 3.
In order to probe the generality of the reactivity pattern
observed so far for reagents 2a؊2v, we also performed sev-
eral reactions using 2-(2-nitrovinyl)thiophene (1b) as a
Michael acceptor. Indeed, as the results given in Table 3
demonstrate, the same reactivity pattern was observed, 2-
(2-nitrovinyl)thiophene (1b) just being a little less reactive
than β-nitrostyrene (1a). The ratio of syn/anti diastereomers
was determined by NMR and in some cases also by HPLC
measurements, which resulted in some different dr values in
Table 2 and Table 4. From the results given in Tables 2 and
3 it follows that formation of the syn diastereomer is
strongly favored, which is consistent with refs.[18Ϫ21] The
absolute configuration of the main products was suggested
in analogy with refs.[18Ϫ21]
We next examined the stereoselectivity of -proline-cata-
lysed Michael additions, and therefore determined the ee of
selected samples by HPLC measurements (Table 4). While
all samples were pure according to TLC and NMR, the
HPLC measurements were complicated by UV-active trace
impurities and the tendency of some samples to slowly de-
compose. Nevertheless, the results given in Table 4 are sig-
nificant and clearly show that only low or medium stereo-
selectivities were obtained, even when 20 mol % of -proline
or a great excess of aldehyde was used (entries 3 and 4).
Thanks to a referee comment we also performed reactions
in four other ionic liquids, namely: 1-butyl-3-methylimida-
zolium tetrafluoroborate ([bmim]BF4), 1,3-dibutylimidazol-
ium bromide ([dbim]Br), 1,3-dibutylimidazolium hexa-
fluorophosphate ([dbim]PF6) and 1-butyl-3-methylimidazo-
lium laurate ([bmim] laurate). Chemical yields were in most
cases very high (95%) although with [bmim] laurate the
yield was 82%. Table 4, entries 20Ϫ23, show that ee values
are similar to those achieved in experiments using
[bmim]PF6 as the solvent, the exception being [bmim] laur-
ate in which 58% ee was achieved. We have to add that this
ionic liquid is very miscible with organic solvents and the
product had to be isolated by flash chromatography on sil-
ica gel.
Comparing our results with those published we can state
that by using an ionic liquid as a solvent we have reached
similar results (dr, ee) to those described by Alexakis,[20]
who used 15 mol % of -proline in DMSO, and by En-
ders,[21] who used 20Ϫ15 mol % of -proline in methanol.
On the other hand our yields are lower that those reported
by Enders.[21] Better results with respect to both yields and
selectivities were only described by Barbas,[18] who used 20
mol % of (S)-2-(morpholinomethyl)pyrrolidine as catalyst
and THF as solvent.
Figure 3. Structure of products
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Eur. J. Org. Chem. 2004, 1577Ϫ1583

Michael Additions of Aldehydes and Ketones
FULL PAPER
β-Nitrostyrene (1a) proved to be a better acceptor than
2-(2-nitrovinyl)thiophene (1b), in terms of both reactivity
and selectivity. Aldehydes proved to be much better donors
than ketones, which were themselves better than β-dike-
tones, indane-1,3-dione being the exception. Reactions with
ketones require elevated temperatures to achieve good
yields of products.
Table 3. Results of Michael addition to 2-(2-nitrovinyl)thiophene
1b
Entry
Reagent
t (°C)/Time (h)
Yield (%)
dr (syn/anti)
(NMR)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./24
80/24
room temp./12
room temp./12
room temp./12
room temp./12
room temp./12
73
91
81
85
29
0
5:4
10:1
5:1
5:1
20:1
Ϫ
Ϫ
4:1
10:1
3:2
20:1
8:1
Experimental Section
2f
0
Starting materials, that is nitrostyrene, 2-(2-nitrovinyl)thiophene,
aldehydes and ketones together with -proline and trans-4-hydroxy-
-proline and (R)-(Ϫ)thiazolidine-4-carboxylic acid, were commer-
cial products (Aldrich) and used as received.
2h
2o
2q
2s
2u
42
14
11
70
40
10
11
12
NMR spectra were measured on a Varian Gemini 2000 spec-
trometer operating at 300 MHz; tetramethylsilane was used as an
internal standard. The NMR spectra of the main (syn) isomer are
always given. MS spectra were measured on a Micromass ZMD
ESI (80 eV) system; substances were dissolved in an acetonitrile/
water (80:20) mixture, with the exception of compounds 3d, 4d and
4e, which were dissolved in chloroform, and 100% methanol was
Table 4. Determination of ee of the chosen samples by HPLC
Entry Reagents t (°C) /Time (h) dr (syn/anti) ee (syn) (%)
used as the mobile phase. HPLC was performed on
a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1aϩ2a
1aϩ2b
1aϩ2b
1aϩ2b
1aϩ2c
1aϩ2d
1aϩ2e
1aϩ2h
1aϩ2i
1aϩ2k
1aϩ2n
1aϩ2o
1aϩ2q
1aϩ2r
1bϩ2a
1bϩ2b
1bϩ2c
1bϩ2d
1bϩ2e
1aϩ2b
1aϩ2b
1aϩ2b
1aϩ2b
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./14
70/14
n.d.
12
MerckϪHitachi. HPLC-system with Pump -6200A, UV-Detector
-4000A, RF-Detector RI-71 and software HPLC-Manager D-
6000 using Diacel Chiralpak AD-H 250ϫ4 mm column equipped
with MachereyϪNagel Nucleosil 100Ϫ5 11ϫ3 mm precolumn.
Hexane/2-propanol 90:10 was used as the eluent. A UV detector
was used in most cases, but in the case of cyclic ketones a refractory
detector has to be used. (S)-2-(morpholinomethyl)pyrrolidine was
prepared according to ref.[31], 1-methyl-2,2-dimethyl-4-[(S)-benzyl]-
pyrimidine-5-one (CAT6) was prepared according to ref.[32] and
CAT7 was prepared analogously to CAT6.
Ն25:1
25:1
25:1
‘‘signif.‘‘
‘‘high‘‘
n.d.
2:1
4:1
n.d.
n.d.
n.d.
n.d.
n.d.
2.5:1
3:1
3:1
1.5:1
n.d.
25:1
25:1
25:1
25:1
43
39[a]
42[b]
38
31
3
32[c]
very low[c]
3[d]
80/22
80/22
60
room temp./14
room temp./14
room temp./14
room temp./22
room temp./22
room temp./22
room temp./22
room temp./22
room temp./12
room temp./12
room temp./12
35/12
10[d]
8[d]
General Experimental Procedure: -Proline (5.75 mg, 5 mol %) and
the chosen donor (2) (1.5 equiv.) were added to the degassed ionic
liquid [bmim]PF6 (1 mL) and the mixture was stirred for 15 min at
room temp. Acceptor (1) (1 mmol) was then added and the reaction
mixture was stirred intensively for the chosen time at the chosen
temperature (see Tables). The product was extracted in several por-
tions of diethyl ether and the extract was chromatographed on SiO2
column using hexane/dichloromethane, 2:1 as the eluent when alde-
hydes were used as donors and hexane/ethyl acetate, 4:1 in all other
cases. Products were isolated as pure materials and their structure
was proved by 1H NMR spectra and, in the case of new com-
pounds, also by mass spectrometry.
17[d]
28
25
25
36[c]
5
43[e]
41[f]
35[g]
58[h]
[a]
Reaction was performed with 20 mol % of -proline and 1.5
[b]
equiv. of aldehyde. Reaction was performed with 5 mol % of -
proline and 10 equiv. of aldehyde. ee was determined by HPLC
using a refractometer as detector.
[c]
2-Methyl-4-nitro-3-phenylbutyraldehyde (3a): 1H NMR (300 MHz,
CDCl3): δ ϭ 9.72 (d, J ϭ 1.5 Hz, 1 H), 7.36Ϫ7.29 (m, 3 H),
7.17Ϫ7.16 (m, 2 H), 4.80 (dd, J ϭ 12.9, 5.5 Hz, 1 H), 4.69 (dd, J ϭ
12.9, 9.2 Hz, 1 H), 3.81 (ddd, J ϭ 9.2, 9.2, 5.5 Hz, 1 H), 2.80Ϫ2.75
(m, 1 H), 1.01 (d, J ϭ 7.4 Hz, 3 H), in agreement with ref.[18]
[d]
ee was determined by NMR
[e]
(chiral NMR shift reagent). [bmim]BF4 was used as the solvent.
[f]
[g]
[dbim]Br was used as the solvent. [dbim]PF6 was used as the
[h]
solvent. [bmim] laurate was used as the solvent.
2-Isopropyl-4-nitro-3-phenylbutyraldehyde
(3b):
1H
NMR
Conclusions
(300 MHz, CDCl3): δ ϭ 9.93 (d, J ϭ 2.6 Hz, 1 H), 7.36Ϫ7.29 (m,
3 H), 7.20Ϫ7.18 (m, 2 H), 4.67 (dd, J ϭ 12.5, 4.4 Hz, 1 H), 4.58
(dd, J ϭ 12.5, 10.2 Hz, 1 H), 3.90 (ddd, J ϭ 10.2, 10.2, 4.4 Hz, 1
H), 2.79Ϫ2.75 (m, 1 H), 1.76Ϫ1.69 (m, 1 H), 1.10 (d, J ϭ 7.2 Hz,
3 H), 0.89 (d, J ϭ 7.2 Hz, 3 H), in agreement with ref.[18]
The ionic liquid [bmim]PF6 was shown to be a good sol-
vent for -proline-catalysed Michael additions of different
donors (carbonyl compounds) to β-(nitrovinyl)arenes. Just
5 mol % of -proline are necessary to reach reasonable to
high yields in a short reaction time (1 day instead of 2Ϫ3
days in other solvents). -Proline was found to be the best
among seven catalysts tested.
2-Ethyl-4-nitro-3-phenylbutyraldehyde (3c): 1H NMR (300 MHz,
CDCl3): δ ϭ 9.72 (d, J ϭ 2.6 Hz, 1 H), 7.36Ϫ7.28 (m, 3 H),
7.19Ϫ7.17 (m, 2 H), 4.72 (dd, J ϭ 12.8, 4.9 Hz, 1 H), 4.63 (dd, J ϭ
12.8, 9.7 Hz, 1 H), 3.79 (ddd, J ϭ 9.7, 9.7, 4.9 Hz, 1 H), 2.71Ϫ2.66
Eur. J. Org. Chem. 2004, 1577Ϫ1583
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P. Kotrusz, S. Toma, H.-G. Schmalz, A. Adler
FULL PAPER
(m, 1 H), 1.53Ϫ1.49 (m, 2 H), 0.83 (dd, 3 H, J ϭ 7.5, 7.5 Hz), in 4.395 (d, J ϭ 10.8 Hz, 1 H), 4.282Ϫ4.204 (m, 1 H), 2.298 (s, 3 H),
agreement with ref.[18]
1.944 (s, 3 H), in agreement with ref.[21]
2-(2-Nitro-1-phenylethyl)-1,3-diphenylpropane-1,3-dione (3p): 1H
NMR (300 MHz, CDCl3): δ ϭ 7.876 (dd, J ϭ 7.2, 1.2 Hz, 2 H),
7.847 (dd, J ϭ 7.2, 1.2 Hz, 2 H), 7.58 (m, 2 H), 7.419 (m, 4 H),
7.225 (m, 5 H), 5.849 (d, J ϭ 7.8 Hz, 1 H), 5.008 (d, J ϭ 6.6 Hz,
2 H), 4.658 (m, 1 H). MS (neg. mode): m/z ϭ 372 [M Ϫ Hϩ].
C23H19NO4 (373.41): calcd. C 73.98, H 5.13, N 3.75; found C
74.05, H 5.17, N 3.81.
2-Benzyl-4-nitro-3-phenylbutyraldehyde (3d): 1H NMR (300 MHz,
CDCl3): δ ϭ 9.717 (d, J ϭ 2.1 Hz, 1 H), 7.382Ϫ7.226 (m, 10 H),
4.73 (dd, J ϭ 6, 2.4 Hz, 2 H), 3.836 (m, 1 H), 3.13 (m, 1 H), 2.77
(t, 2 H). MS (neg. mode): m/z ϭ 318 [M ϩ ClϪ]. C17H17NO3
(283.33): calcd. C 72.07, H 6.05, N 4.94; found C 72.37, H 6.09,
N 4.98.
2-Methyl-4-nitro-2,3-diphenylbutyraldehyde
(3e):
1H
NMR
2-(2-Nitro-1-phenylethyl)-1-phenylbutane-1,3-dione (3q): 1H NMR
(300 MHz, CDCl3): δ ϭ 8.031Ϫ7.27 (m, 10 H), 5.203 (m, 1 H),
4.781 (m, 2 H), 4.540 (m, 1 H, major), 4.416 (m, 1 H, minor), 2.231
(s, 1 H, minor), 1.940 (s, 1 H, major), in agreement with ref.[36]
(300 MHz, CDCl3): δ ϭ 9.558 (d, J ϭ 2.0 Hz, 1 H), 7.945Ϫ7.280
(m, 10 H), 5.065 (dd, J ϭ 11.7, 1.2 Hz, 1 H), 4.822 (dd, J ϭ 9.6,
3.6 Hz, 1 H), 4.222 (dd, J ϭ 11.4, 3.6 Hz, 1 H), 9.717 (s, 3 H), in
agreement with ref.[33]
1
2-(2-Nitro-1-phenylethyl)cyclobutanone (3g): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.348Ϫ7.202 (m, 5 H), 5.101Ϫ5.044 (dd, J ϭ 12.6,
4.2 Hz, 1 H), 4.678Ϫ4.603 (dd, J ϭ 9.9, 2.7 Hz, 1 H), 3.725Ϫ3.620
(m, 2 H), 3.119Ϫ2.982 (m, 2 H), 2.082Ϫ2.067 (m, 1 H), 1.731Ϫ1.67
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): 137.166, 129.317,
129.302, 128.377, 127.766, 127.750, 77.710, 60.100, 44.685, 44.483,
16.043 ppm. MS (neg. mode): m/z ϭ 220 [M Ϫ Hϩ]. C12H13NO3
(219.24): calcd. C 65.74, H 5.98, N 6.39; found C 65.79, H 6.02,
N 6.31.
2-(2-Nitro-1-phenylethyl)indan-1,3-dione (3r): H NMR (300 MHz,
CDCl3): δ ϭ 7.876Ϫ7.739 (m, 5 H), 7.259Ϫ7.153 (m, 5 H), 5.335
(dd, J ϭ 13.5, 5.1 Hz, 1 H), 5.085 (dd, J ϭ 13.5, 7.5 Hz, 1 H),
4.438 (m, 1 H), 3.450 (d, J ϭ 3.6 Hz, 1 H), in agreement with ref.[37]
2-(2-Nitro-1-phenylethyl)malononitrile (3s): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.489Ϫ7.340 (m, 5 H), 4.955 (dd, J ϭ 11.4, 8.1 Hz,
2 H), 4.435 (d, J ϭ 5.7 Hz, 1 H), 7.876 (m, 1 H), in agreement
with ref.[38]
Methyl 2-Cyano-4-nitro-3-phenylbutyrate (3t): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.403Ϫ7.304 (m, 5 H), 5.000Ϫ4.844 (m, 2 H),
4.228Ϫ4.159 (m, 1 H), 4.150 (d, J ϭ 12 Hz, 1 H major), 3.950 (d,
J ϭ 12 Hz, 1 H, minor), 3.785 (s, 3 H, minor), 3.697 (s, 3 H, major),
in agreement with ref.[39]
1
2-(2-Nitro-1-phenylethyl)cyclopentanone (3h): H NMR (300 MHz,
CDCl3): δ ϭ 7.320Ϫ7.149 (m, 5 H), 5.328 (dd, J ϭ 12.9, 7.5 Hz, 1
H), 5.032 (d, J ϭ 7.5 Hz, 1 H), 4.718 (dd, J ϭ 12.9, 9.9 Hz, 1 H),
3.833 (m, 1 H, minor), 3.686 (m, 1 H, major), 2.411Ϫ0.902 (m, 6
H, cycl), in agreement with ref.[34]
2-Acetyl-2-(2-nitro-1-phenylethyl)cyclopentanone (3u): 1H NMR
(300 MHz, CDCl3): δ ϭ 7.300Ϫ7.28 (m, 5 H), 4.868 (dd, J ϭ 11.4,
2.1 Hz, 1 H), 4.521 (dd, J ϭ 13.5, 3.9 Hz, 1 H), 4.419 (dd, J ϭ
13.5, 3.9 Hz, 1 H), 2.613 (m, 1 H), 2.337 (s, 3 H), 2.241 (m, 1 H),
2.037 (m, 1 H), 1.719 (m, 3 H), in agreement with ref.[40]
2-(2-Nitro-1-phenylethyl)cyclohexanone (3i): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.325Ϫ7.155 (m, 5 H), 4.673 (dd, J ϭ 9.9, 2.4 Hz, 1
H), 4.096 (m, 1 H, minor), 3.770 (m, 1 H, major), 2.735Ϫ1.264 (m,
9H cycl), in agreement with ref.[20]
2-(2-Nitro-1-phenylethyl)cycloheptanone (3j): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.336Ϫ7.160 (m, 5 H), 4.658 (dd, J ϭ 8.1, 4.8 Hz, 2
H), 3.691 (m, 1 H), 3.036 (m, 1 H), 2.548 (m, 3 H), 1.904Ϫ1.509
(m, 5 H), 1.246 (m, 2 H), in agreement with ref.[34]
2-Methyl-4-nitro-3-(thiophen-2-yl)butyraldehyde (4a): 1H NMR
(300 MHz, CDCl3): δ ϭ 9.703 (d, J ϭ 1.2 Hz, 1 H, major), 9.630
(d, J ϭ 1.2 Hz, 1 H, minor), 7.255 (d, J ϭ 2.4 Hz, 1 H), 6.946 (m,
2 H), 4.795 (m, 2 H), 4.234 (m, 1 H), 2.815 (m, 1 H), 1.128 (d, J ϭ
7.2 Hz, 3 H, minor), 1.148 (d, J ϭ 7.2 Hz, 3 H, major). MS (neg.
mode): m/z ϭ 212 [M Ϫ Hϩ]. C9H11NO3S (213.26): calcd. C 50.69,
H 5.20, N 6.57, S 15.04; found C 50.75, H 5.28, N 6.62, S 15.24.
5-Nitro-4-phenylpentane-2-one (3k): 1H NMR (300 MHz, CDCl3):
δ ϭ 7.334Ϫ7.200 (m, 5 H), 4.688 (dd, J ϭ 6.9, 3.5 Hz, 1 H), 4.608
(dd, J ϭ 7.5, 3.5 Hz, 1 H), 4.008 (m, 1 H), 2.931 (d, J ϭ 6.9 Hz, 2
H), 2.120 (s, 3 H), in agreement with ref.[20]
2-Isopropyl-4-nitro-3-(thiophen-2-yl)butyraldehyde (4b): 1H NMR
(300 MHz, CDCl3): δ ϭ 9.913 (d, J ϭ 2.4 Hz, 1 H, major), 9.630
(d, J ϭ 2.4 Hz, 1 H, minor), 7.263 (d, J ϭ 5.7 Hz, 1 H), 6.937 (m,
2 H), 4.236 (m, 1 H), 2.822 (dd, J ϭ 4.5, 1.8 Hz, 1 H), 1.919 (m, 1
H), 1.169 (d, J ϭ 6.9 Hz, 3 H), 0.936 (d, J ϭ 6.9 Hz, 3 H), in
agreement with ref.[18]
2-Methyl-7-nitro-6-phenylheptane-4-one (3l): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.322Ϫ7.221 (m, 5 H), 4.663 (dd, J ϭ 16.8, 6.9 Hz, 1
H), 4.604 (dd, J ϭ 16.8, 6.9 Hz, 1 H), 4.018 (m, 1 H), 2.864 (dd,
J ϭ 2.1, 1.8 Hz, 2 H), 2.216 (dd, J ϭ 7.5, 2.7 Hz, 2 H), 2.070 (m,
1 H), 0.848 (d, J ϭ 6.6 Hz, 6 H). MS (neg. mode): m/z ϭ 248 [M
Ϫ Hϩ]. C14H19NO3 (249.31): calcd. C 67.45, H 7.68, N 5.62; found
C 67.51, H 7.62, N 5.59.
2-Ethyl-4-nitro-3-(thiophen-2-yl)butyraldehyde (4c): 1H NMR
(300 MHz, CDCl3): δ ϭ 9.722 (d, J ϭ 1.8 Hz, 1 H, major), 9.616
(d, J ϭ 1.8 Hz, 1 H, minor), 7.244 (d, J ϭ 5.7 Hz, 1 H), 6.953 (m,
2 H), 4.725 (m, 2 H), 4.190 (m, 1 H), 2.707 (m, 1 H), 1.663 (q, 2
H), 1.039 (t, 3 H, minor), 0.944 (t, 3 H, major). MS (neg. mode):
m/z ϭ 226 [M Ϫ Hϩ]. C10H13NO3S (227.28): calcd. C 52.85, H
5.77, N 6.16, S 14.11; found C 52.90, H 5.74, N 6.10, S 14.17.
2,2-Dimethyl-6-nitro-5-phenylhexane-3-one
(3m):
1H
NMR
(300 MHz, CDCl3): δ ϭ 7.631 (m, 5 H), 4.120 (m, 2 H), 3.665 (t,
2 H), 3.065 (m, 1 H), 0.905 (s, 9 H), in agreement with ref.[35]
4-Methyl-6-nitro-5-phenylhexane-3-one (3n): 1H NMR (300 MHz,
CDCl3): δ ϭ 7.333Ϫ7.239 (m, 3 H), 7.174Ϫ7.148 (m, 2 H), 4.629
(dd, J ϭ 12.9, 5.1 Hz, 2 H), 3.704 (m, 1 H), 3.001 (m, 1 H), 2.575
(m, 1 H), 2.430 (m, 1 H), 1.075 (t, 3 H), 0.970 (d, J ϭ 7.2 Hz, 3
H), in agreement with ref.[20]
2-Benzyl-4-nitro-3-(thiophene-2-yl)butyraldehyde (4d): 1H NMR
(300 MHz, CDCl3): δ ϭ 9.707 (d, J ϭ 1.8 Hz, 1 H), 7.296Ϫ7.229
(m, 5 H), 7.126 (d, 1 H), 6.984 (m, 2 H), 4.713 (m, 2 H), 4.236 (m,
1 H), 3.137 (m, 1 H), 2.869 (d, J ϭ 7.5 Hz, 2 H). MS (neg. mode):
m/z ϭ 324 [M ϩ ClϪ]. C15H15NO3S (289.36): calcd. C 62.26, H
5.23, N 4.84, S 11.08; found C 62.22, H 5.29, N 4.89, S 11.14.
3-(2-Nitro-1-phenylethyl)pentane-2,4-dione
(3o):
1H
NMR
(300 MHz, CDCl3): δ ϭ 7.367Ϫ7.169 (m, 5 H), 4.620 (m, 2 H),
1582
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1577Ϫ1583

Michael Additions of Aldehydes and Ketones
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7.388Ϫ7.128 (m, 6 H), 6.808 (dd, J ϭ 5.1, 3.6 Hz, 1 H), 6.684 (d,
J ϭ 2.7 Hz, 1 H), 4.923 (dd, J ϭ 11.4, 1.8 Hz, 1 H), 4.707 (dd, J ϭ
11.4, 1.8 Hz, 1 H), 4.532 (2d, 1 H, J ϭ 3.6 Hz), 1.603 (s, 3 H). MS
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2-[2-Nitro-1-(thiophen-2-yl)ethyl]cyclopentanone (4h): 1H NMR
(300 MHz, CDCl3): δ ϭ 7.22 (d, J ϭ 1 Hz, 1 H), 6.946 (d, J ϭ
3.3 Hz, 1 H), 6.874 (d, J ϭ 6 Hz, 1 H), 4.969 (dd, J ϭ 12.9, 6.3 Hz,
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9.3 Hz), 4.780 (m, 3 H), 2.480 (s, 3 H,minor), 2.046 (s, 3 H, major).
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Acknowledgments
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[37]
´
We are grateful to Dr. E. Solcaniova and her staff for NMR meas-
urements. This work was supported by the Slovak Grant Agency
VEGA, grant No. 1/0072/03.
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Received October 13, 2003
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Eur. J. Org. Chem. 2004, 1577Ϫ1583
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1583