Self-assembly of organocatalysts for the enantioselective Michael addition of aldehydes to nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2009.12.008

A proline-thiourea self-assembled organocatalyst is described as a good catalyst for the enantioselective nitro-Michael addition of aldehydes to nitroalkenes. The reaction is efficient with 5% of the thiourea, to give moderate to good enantioselectivity (up to 76% ee). High syn-selectivity was obtained with both branched and unbranched aliphatic aldehydes. This is the first example of self-assembly of organocatalysts with an achiral additive in a Michael addition wherein aldehydes are utilized as donors.

Full text of DOI:10.1016/j.tetasy.2009.12.008

Tetrahedron: Asymmetry 21 (2010) 112–115
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Self-assembly of organocatalysts for the enantioselective Michael addition
of aldehydes to nitroalkenes
*
Ayhan S. Demir , Serkan Eymur
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A proline–thiourea self-assembled organocatalyst is described as a good catalyst for the enantioselective
nitro-Michael addition of aldehydes to nitroalkenes. The reaction is efficient with 5% of the thiourea, to
give moderate to good enantioselectivity (up to 76% ee). High syn-selectivity was obtained with both
branched and unbranched aliphatic aldehydes. This is the first example of self-assembly of organo-
catalysts with an achiral additive in a Michael addition wherein aldehydes are utilized as donors.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 November 2009
Accepted 21 December 2009
Available online 12 January 2010
1. Introduction
formed through the self-assembly of simple a-amino acids and
alkaloid thiourea derivatives could be used as efficient catalysts
for the nitro-Michael addition of ketones and nitroalkenes.8 This
approach is not only beneficial in avoiding chemical synthesis
but it is also useful for constructing libraries of structurally diverse
catalysts. To the best of our knowledge, there has been no report on
the application of these types of self-assembly of organocatalysts
with an achiral additive in a Michael addition wherein aldehydes
are utilized as donors.
We have previously shown the proof-of-principle results of pro-
line-catalyzed direct aldol reactions between cyclic ketones and
aldehydes using 1,3-bis[3,5-bis(trifluoromethyl)phenyl] thiourea
A as the additive.9 We proposed that the reaction would proceed
according to a modified Houk–List model,10 in which the carboxyl-
ate moiety of the proline forms an assembly with the thiourea, in
turn enhancing the reactivity and selectivity of the catalyst.
Furthermore, the thiourea is treated as a non-polar counterpart
to proline, amplifying its solubility limits in non-polar solvents,
such as hexane or toluene (Fig. 1).
In recent years, organocatalysis, which in organic reactions are
catalyzed by small organic molecules, has expanded rapidly.1 The
Michael reaction of carbon-centered nucleophiles to nitroalkenes
is one such reaction that is catalyzed by organocatalysts.2 Nitroalk-
anes are crucial intermediates in organic synthesis due to their
ability to transform the nitro group into other useful functional-
ities.3 After the first organocatalytic asymmetric Michael addition
of aldehydes to nitroalkenes was reported by Betancort and
Barbas,4 extraordinary progress has been sought in order to find
more selective and efficient catalytic systems for these Michael
reactions.5 Even though
L-proline, which is a widely distributed
amino acid, has been described as a catalyst for asymmetric
Michael reactions with aldehydes as the donor, only poor enanti-
oselectivity is typically observed.6,4b The enolates of aldehydes
have reactions that are more difficult to manage, with polymeriza-
tion and aldolization processes competing. Proline-derived or
pyrrolidine-based catalytic systems have been shown to be suc-
cessful for this transformation in both ketones and aldehydes.
Nonetheless, they are generally more complex and, therefore, have
to be prepared by a multistep synthesis. Thus, the development of
more-effective asymmetric catalysts in terms of both enantioselec-
tivity and a substrate scope is still desirable.
CF3
A
B
CF3
In 2007, Clarke and Funtes reported the first example of the
self-assembly of organocatalysts for the Michael addition of ke-
tones to nitroalkenes, wherein the addition of achiral additives to
a chiral organocatalyst host can transform an unselective catalyst
into a highly effective one through hydrogen-bonding interac-
tions.7 Zhao and Mandal reported that organocatalysts that were
HN
HN
CF3
O
N
HN
HN
CF3
H
O
S
O
S
R
H
F3C
CF3
F3C
CF3
* Corresponding author. Tel.: +90 3122103242; fax: +90 3122101280.
E-mail address: asdemir@metu.edu.tr (A.S. Demir).
Figure 1. Our previous study.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.008

A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 112–115
113
Table 2
The possibility of fine-tuning these proline–thiourea interac-
The enantioselective Michael addition of aldehydes to nitroalkenes
tions also presents a possible strategy for asymmetric catalyst
development.
Entry
Aldehyde 1
R0
Yield (%)
syn/anti
ee (%)
R
1
2
–CH3
a
–CH3
a
CH3
a
–CH2CH3
b
–CH2CH3
b
–CH2CH2CH3
c
–CH2CH2CH3
c
–CH2CH2CH3
c
–CH(CH3)2
d
–CH(CH3)2
d
–CH3, –CH3
e
–CH3, –CH3
e
H
85
79
80
77
79
86
50
65
88
80
66
87
12:1
11:1
10:1
20:1
17:1
15:1
14:1
15:1
38:1
35:1
—
76 3a
60 3b
60 3c
67 3d
69 3e
76 3f
44 3g
50 3h
75 3i
60 3j
72 3k
23 3k
2. Result and discussion
4-OMe
4-Br
H
Herein, we report the results of the enantioselective Michael
addition of aldehydes to nitroalkenes catalyzed by a proline–thio-
urea host–guest complex. To optimize the reaction conditions, the
reaction of isovaleraldehyde and trans-b-nitrostyrene was investi-
gated as a model (Scheme 1).
3
4
5
4-Br
H
O
6
O
Ph
*
Proline + thiourea A
Ph
NO2
NO2
*
7
4-OMe
4-Br
H
solvent, rt, 36h
8
1
2
3
9
Scheme 1.
10
11a
12b
4-Br
H
The reaction was performed at rt for 36 h in the presence of
L
-proline and 1,3-bis[3,5-bis(trifluoromethyl)phenyl] thiourea. During
the studies, some representative illustrative solvents were screened;
the screening results are summarized in Table 1.
H
—
As can be seen, our first attempt in hexane gave a good conver-
sion but low enantioselectivity (entry 1). Under the same reaction
conditions, a similar trend was observed for the other solvents,
such as dioxane and chloroform. Examination of the solvents
showed that the best enantioselectivity was obtained when the
solvent benzene was used as the solvent (entries 9 and 11). For fur-
ther optimization of the reaction condition, we screened the effect
of an equivalent of the donor, and catalyst loading. From a practical
point of view, the Michael addition of aldehydes to b-nitrostyrene
usually requires a large (10-fold) excess of the donor, due to com-
peting aldol pathways. However, in the present study, the reaction
worked with only 3 equiv of the donor. Further investigation
showed that by using only 5% thiourea, the reaction produced a
good conversion without a decrease in enantioselectivity. When
the reaction was carried out without the thiourea additive, the
reaction was very slow, with a low stereoselectivity (Table 1,
entry 12). These results obviously demonstrate the influential ef-
fect of the thiourea on the reactivity and selectivity.
With the optimized conditions in hand, the generality of the
reaction was then examined. Various nitroalkenes and aldehydes
were tested under the optimized reaction conditions, in which
the results are shown in Table 2.
Unbranched aldehydes, such as propionaldehyde 1a, butanal
1b, and pentanal 1c, gave the 1,4-addition in good yields and mod-
erate to good enantioselectivities with excellent diastereoselectiv-
ities. We then continued to evaluate the scope of the reaction by
O
*
Ar
*
NO2 L-proline + thiourea A
O
20%
5%
NO2
benzene, rt
R'
R
R
1
2
3
a
20:20% Proline–thiourea was used.
b
DMSO was used as a solvent, 20:0% Proline–thiourea was used, see Ref. 5d.
testing the Michael addition of isovaleraldehyde 1d to various
nitroalkenes, in which a good yield and moderate to good enantio-
selectivities were observed. On the other hand,
a-branched alde-
hydes, isobutyraldehyde 1e, led to a good isolated yield (66%)
and good enantioselectivity (72%) (Table 2, entry 11). The reactions
with nitroalkenes bearing not only phenyl, but also electron-rich
and electron-deficient aryl groups on the nitroalkene proceeded
efficiently, with a high diastereoselectivity. In all the cases, as little
as 5% thiourea was adequate to obtain the best ee values.
To explain the higher syn-diastereoselectivities and the enanti-
oselectivities with respect to proline, we propose a TS based on
Seebach’s model11 as can be seen in Figure 2. In this model, the
preferential formation of the anti-enamine with the double bond
was oriented away from the bulky substituent at the 2-position
of the pyrrolidine ring. Subsequently, the enamine reacts with
Table 1
Solvent screening for the enantioselective Michael reaction of 1 and 2
Entry
Cat. (%)
Solvent
Equiv of aldehyde
Conv. (%)
syn/anti
ee (%)
proline:urea
1
2
3
4
5
6
7
8
9
20:20
20:20
20:20
20:20
20:10
20:20
20:20
20:20
20:10
20:5
Hexane
Toluene
10
10
10
3
3
3
3
3
3
3
94
83
87
86
85
95
94
99
99
98
90
66
36:1
65:1
41:1
40:1
40:1
38:1
36:1
30:1
41:1
39:1
41:1
15:1
25
29
35
32
32
35
53
76
72
76
72
nd
Chloroform
Chloroform
Chloroform
Dioxane
Cyclohexane
Benzene
Benzene
Benzene
Benzene
Benzene
10
11
12
5:5
20:0
3
3

114
A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 112–115
F3C
4.2.1. 2-Methyl-4 nitro-3-phenylbutyraldehyde 3a
From propionaldehyde 1a and nitrostyrene 2a at rt according to
the general procedure; syn/anti = 12/1; ee = 76%; the enantiomeric
excess was determined by HPLC (Chiralcel OD-H), Hex: iPrOH
80:20, UV 220 nm, 0.8 ml/min, syn: tR = 17.7 (minor) and tR = 22.6
(minor). 1H NMR (400 MHz, CDCl3): d = 9.66 (d, J = 1.7, 1H), 7.33–
7.21 (m, 3H), 7.14–7.10 (m, 2H), 4.76 (dd, J = 5.5, 12.7, 1H), 4.65
(dd, J = 9.3, 12.7, 1H), 3.76 (td, J = 5.5, 9.2, 1H), 2.78–2.70 (m, 1H),
1.01 (d, J = 7.3, 3H).
CF3
O
O
H
H
N
N
O
N
S
N
R
H
O
CF3
Ph
F3C
4.2.2. 3-(4-Methoxyphenyl)-2-methyl-4-nitrobutyraldehyde 3b
From propionaldehyde 1a and trans-4-methoxy-b-nitrostyrene
2b at rt according to the general procedure; syn/anti = 11/1;
ee = 60%; the enantiomeric excess was determined by HPLC (Chi-
ralcel OD-H), Hex: iPrOH 85:15, UV 254 nm, 1.0 ml/min, syn:
tR = 19.8 (minor) and tR = 22.2 (minor). 1H NMR (400 MHz, CDCl3):
d = 9.69 (d, J = 1.7, 1H), 7.12–7.03 (m, 3H), 6.85–6.80 (m, 2H), 4.78–
4.67 (m, 1H), 4.60 (dd, J = 9.4, 12.5, 1H), 3.76 (s, 3H), 2.81–2.64 (m,
1H), 1.18 (d, J = 7.2, 1H), 1.01 (d, J = 7.3, 3H).
Figure 2. Possible transition state.
the nitro olefin via an acyclic synclinal transition state. A bulky
substituent at the 2-position of the pyrrolidine ring plays two
important roles: it favors the selective formation of the anti-enam-
ine and also shields its Re-face.
3. Conclusion
4.2.3. 3-(4-Bromophenyl)-2-methyl-4-nitro-butyraldehyde 3c
From propionaldehyde 1a and trans-4-bromo-b-nitrostyrene 2c
at rt according to the general procedure; syn/anti = 10/1; ee = 60%;
the enantiomeric excess was determined by HPLC (Chiralcel
OD-H), Hex: iPrOH 8:2, UV 254 nm, 0.8 ml/min, syn: tR = 17.7 (min-
or) and tR = 22.6 (minor). 1H NMR (400 MHz, CDCl3): d = 9.70 (d,
J = 1.5, 1H), 7.52–7.45 (m, 2H), 7.13–7.03 (m, 2H), 4.80 (dd,
J = 5.2, 12.8, 1H), 4.65 (dd, J = 9.6, 12.8, 1H), 3.91–3.67 (m, 1H),
2.93–2.62 (m, 1H), 1.01 (d, J = 7.3, 3H).
In conclusion, the results from our investigations show that the
additon of achiral thiourea to an L-proline have an enormous effect
on solubility reactivity and selectivity, even in an unconventional
non-polar reaction medium, thus eliminating the need to use low
temperatures. These self-assembled organocatalysts are good cata-
lysts for the enantioselective nitro-Michael addition of aldehydes
to nitroalkenes. The reaction is efficient with just 5% thiourea, in
which moderate to good enantioselectivity and high syn-selectivity
was obtained in both branched and unbranched aliphatic alde-
hydes. This is the first example of self-assembly of organocatalysts
with an achiral additive in a Michael addition wherein aldehydes
are utilized as donors.
4.2.4. 2-Ethyl-4-nitro-3-phenyl butyraldehyde 3d
From butanal 1b and nitrostyrene 2a at rt according to the gen-
eral procedure; syn/anti = 20/1; ee = 67%; the enantiomeric excess
was determined by HPLC (Chiralcel OD-H), Hex: iPrOH 80:20, UV
237 nm, 0.8 ml/min, syn: tR = 16.2 (minor) and tR = 17.5 (major).
1H NMR (400 MHz, CDCl3): d = 9.65 (d, J = 2.6 Hz, 1H), 7.30–7.19
(m, 3H), 7.10–7.12 (m, 2H), 4.65 (dd, J = 12.8, 4.9 Hz, 1H), 4.56
(dd, J = 12.8, 9.7 Hz, 1H), 3.72 (ddd, J = 9.7, 9.7, 4.9 Hz, 1H), 2.66–
2.58 (m, 1H), 1.48–1.38 (m, 2H), 0.76 (dd, J = 7.5, 7.5 Hz, 3H).
4. Experimental section
4.1. General
All commercially available reagents were used without further
purification. Purification of products was carried out by flash col-
umn chromatography using Silica Gel 60. Analytical thin layer
chromatography was performed on aluminum sheets precoated
with Silica Gel 60F254. Visualization was accomplished with UV
light and anisaldehyde followed by heating.
4.2.5. 3-(4-Bromophenyl)-2-ethyl-4-nitrobutanal 3e
From butanal 1b and trans-4-bromo-b-nitrostyrene 2c at rt
according to the general procedure; syn/anti = 17/1; ee = 69%; the
enantiomeric excess was determined by HPLC (Chiralcel AD-H),
Hex: iPrOH 98.5:1.5, UV 237 nm, 1.0 ml/min, syn: tR = 33.5 (major)
and tR = 59.4 (minor). 1H NMR (400 MHz, CDCl3): d = 9.65 (d,
J = 2.3 Hz, 1H;), 7.43 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H),
4.67 (dd, J = 4.8 Hz, 12.8 Hz, 1H), 4.56 (dd, J = 9.9 Hz, 12.8 Hz, 1H),
3.72 (dt, J = 4.8 Hz, 9.9 Hz, 1H), 2.62 (m, 1H), 1.53–1.46 (m, 2H),
0.77 (t, J = 7.5 Hz, 3H).
4.2. General procedure for the enantioselective Michael
addition of aldehydes to nitroalkenes
Proline (0.1 mmol, 11.5 mg), thiourea A (0.025 mmol, 12.5 mg),
and 3.2 ml of benzene were placed in a screw-capped vial. Then
aldehyde (1.5 mmol) was added, in which the resulting mixture
was stirred for 30 min at ambient temperature followed by the
addition of nitroalkene (0.50 mmol), wherein stirring was contin-
ued until the completion of the reaction (TLC monitoring). After
completion of the reaction, the reaction mixture was treated with
a saturated aqueous ammonium chloride solution and the whole
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried and concentrated to give a crude residue,
which was purified by column chromatography over silica gel
using hexane–ethyl acetate as an eluent to afford a pure product.
Diastereoselectivity and conversion were determined by 1H NMR
analysis of the crude product. The enantiomeric excess (ee) of 3
was determined by chiral-phase HPLC analysis. The absolute con-
figuration of the products was determined by comparing the val-
ues with those previously reported in the literature.
4.2.6. 2-(2-Nitro-1-phenylethyl)pentanal 3f
From pentanal 1c and nitrostyrene 2a at rt according to the gen-
eral procedure; syn/anti = 15/1; ee = 76%; the enantiomeric excess
was determined by HPLC (Chiralcel OD-H), Hex: iPrOH 90:10, UV
220 nm, 1.0 ml/min, syn: tR = 16.2 (minor) and tR = 18.7 (major).
1H NMR (400 MHz, CDCl3): d = 9.66 (d, J = 2.8, 1H), 7.34–7.24 (m,
3H), 7.16–7.11 (m, 2H), 4.70–4.56 (m, 2H), 3.73 (td, J = 5.3, 9.5,
1H), 2.67 (tt, J = 3.2, 9.5, 1H), 1.50–1.40 (m, 1H), 1.37–1.21 (m,
2H), 1.20–1.06 (m, 1H), 0.77 (t, J = 7.1, 3H).
4.2.7. 2-(1-(4-Methoxyphenyl)-2-nitroethyl)pentanal 3g
From pentanal 1c and trans-4-methoxy-b-nitrostyrene 2b at rt
according to the general procedure; syn/anti = 14/1; ee = 44%; the
enantiomeric excess was determined by HPLC (Chiralcel OD-H),
Hex: iPrOH 90:10, UV 237 nm, 1.0 ml/min, syn: tR = 20.4 (minor)

A. S. Demir, S. Eymur / Tetrahedron: Asymmetry 21 (2010) 112–115
115
and tR = 22.9 (minor). 1H NMR (400 MHz, CDCl3): d = 9.63 (d,
Acknowledgments
J = 3.3 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 9.0, 2H), 4.62
(dd, J = 5.4, 12.6 Hz, 1H), 4.52 (dd, J = 9.3, 12.3 Hz, 1H), 3.71 (s,
3H), 3.65 (dt, J = 5.7, 9.9 Hz, 1H), 2.60 (dt, J = 3.0, 9.3 Hz, 1H),
1.49–1.10 (m, 4H), 0.75 (t, J = 6.9 Hz, 3H).
We gratefully acknowledge the Scientific and Technological
Research Council of Turkey (TUBITAK), the Turkish Academy of
Sciences (TUBA), and the Middle East Technical University
(METU).
4.2.8. 2-(1-(4-Bromophenyl)-2-nitroethyl)pentanal 3h
From pentanal 1c and trans-4-bromo-b-nitrostyrene 2c at rt
according to the general procedure; syn/anti = 15/1; ee = 50%; the
enantiomeric excess was determined by HPLC (Chiralcel OD-H),
Hex: iPrOH 90:10, UV 220 nm, 1.0 ml/min, syn: tR = 20.5 (minor)
and tR = 21.7 (minor). 1H NMR (400 MHz, CDCl3): d = 9.63 (d,
J = 2.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H),
4.63 (dd, J = 5.1, 12.9 Hz, 1H), 4.54 (dd, J = 9.9, 13.2 Hz, 1H), 3.68
(dt, J = 4.8, 9.6 Hz, 1H), 2.62 (dt, J = 3.3, 9.3 Hz, 1H), 1.46–1.05 (m,
4H), 0.75 (t, J = 7.2 Hz, 3H).
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K.; Uudsemaa, M.; Tamm, T.; Kanger, T.; Lopp, M. J. Org. Chem. 2009, 74, 3772–
3775; (m) Demir, A. S.; Sesenoglu, O.; Ulku, D.; Arici, C. Helv. Chim. Acta 2003,
86, 91–105.
4.2.10. 3-(4-Bromophenyl)-2-isopropyl-4-nitrobutanal 3j
From isovaleraldehyde 1d and trans-4-bromo-b-nitrostyrene 2c
at rt according to the general procedure; syn/anti = 35/1; ee = 60%;
the enantiomeric excess was determined by HPLC (Chiralcel
OD-H), Hex: iPrOH 90:10, UV 220 nm, 1.0 ml/min, syn: tR = 15.7
(minor) and tR = 17.2 (minor). 1H NMR (400 MHz, CDCl3): d = 9.84
(d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.4 Hz, 1.5 Hz, 2H), 7.01 (dd,
J = 8.4 Hz, 1.5 Hz, 2H), 4.65–4.59 (m, 1H), 4.52–4.44 (m, 1H), 3.82
(m, 1H), 2.71–2.67 (m, 1H), 1.64 (m, 1H), 1.04 (d, J = 7.2 Hz, 3H),
0.80 (d, J = 7.2 Hz, 3H).
6. (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975–2978; (b) Enders, D.; Seki, A.
Synlett 2002, 26–28.
4.2.11. 3-(4-Bromophenyl)-2,2-dimethyl-4-nitrobutanal 3k
From isobutyraldehyde 1e and nitrostyrene 2a at rt according to
the general procedure; ee = 72%; the enantiomeric excess was
determined by HPLC (Chiralcel OD-H), Hex: iPrOH 80:20, UV
220 nm, 1.0 ml/min, syn: tR = 11.5 (minor) and tR = 16.6 (minor).
1H NMR (400 MHz, CDCl3): d = 9.53 (s, 1H), 7.30–7.19 (m, 5H),
4.86 (t, J = 12.9 Hz, 1H), 4.70 (d, J = 12.9 Hz, 1H), 3.80 (d,
J = 11.7 Hz, 1H), 1.13 (s, 3H), 1.00 (s, 3H).
7. Clarke, M. L.; Fuentes, J. A. Angew. Chem., Int. Ed. 2007, 46, 930–933.
8. Mandal, T.; Zhao, C.-G. Angew. Chem., Int. Ed. 2008, 47, 7714–7717.
9. Reis, Ö.; Eymur, S.; Reis, B.; Demir, A. S. Chem. Commun. 2009, 9, 1088–1090.
10. (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125,
16–17; (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc.
2003, 125, 2475–2479.
11. Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413–1423.