Direct asymmetric aldol condensation catalyzed by aziridine semicarbazide zinc(II) complexes

Article abstract of DOI:10.1016/j.tetlet.2014.02.131

Previously obtained semicarbazides derived from N-triphenylmethyl- aziridine-2-carbohydrazide were explored as ligands in Zn(II) catalyzed diastereo- and enantioselective direct aldol reactions. Complexes of aziridine-semicarbazides with Zn(II) were effic

Full text of DOI:10.1016/j.tetlet.2014.02.131

Tetrahedron Letters 55 (2014) 2373–2375
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Tetrahedron Letters
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Direct asymmetric aldol condensation catalyzed by aziridine
semicarbazide zinc(II) complexes
⇑
´
Adam M. Pieczonka, Stanisław Lesniak, Michał Rachwalski
´
´
University of Łódz, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 Łódz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously obtained semicarbazides derived from N-triphenylmethyl-aziridine-2-carbohydrazide were
explored as ligands in Zn(II) catalyzed diastereo- and enantioselective direct aldol reactions. Complexes
of aziridine-semicarbazides with Zn(II) were efficient catalysts in reactions of acetone and hydroxyace-
tone with NO2-substituted aromatic aldehydes in the presence of water.
Received 11 September 2013
Revised 18 December 2013
Accepted 26 February 2014
Available online 11 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Chiral ligands
Aldol condensation
Aziridines
An important reaction type in modern organic synthesis is the
enantioselective carbon–carbon bond formation. Zinc(II)
complexes in combination with aziridine ligands are powerful
tools in several stereocontrolled reactions such as cycloaddition,1
nitroaldol (Henry) reactions,2 and arylations of aldehydes.3 The
aldol condensation is a key tool for the construction of simple b-
hydroxy carbonyl building blocks, and the ability to control the
enantioselectivity of this process is the principal behind the syn-
thesis of many organic and bioorganic systems. Zinc(II) complexes
which catalyze the aldol reaction are known in the literature.4
On the other hand, aziridine derivatives are versatile ligands,
because they can form very strong interactions with Zn(II). More
importantly, they are particularly useful in numerous enantiose-
lective carbon–carbon bond-forming reactions such as the addition
of diethylzinc and phenylethynylzinc to aldehydes5,6 and to
enones.7
isocyanates yielding enantiomerically pure semicarbazides 2,
quantitatively (Scheme 1). Compounds 2 were previously tested
in asymmetric diethylzinc and phenylethynylzinc additions to aro-
matic aldehydes proving to be efficient catalysts. In continuation of
this research, we decided to test ligands 2 in asymmetric aldol
condensations.
The first experiments (Table 1) were performed with p-nitro-
benzaldehyde in acetone in the presence of 5 mol % of ligand 2a.
After 72 h, only starting materials were isolated. Subsequent
experiments were carried out with the addition of 5 mol % of
Zn(OTf)2 (entry 2) and 10% of water (entry 3). Only in the third case
we obtained the desired product in 23% yield. The method was
modified and a 2.9:0.1 mixture of acetone/water was used to
increase the solubility of the ligand and the desired product was
obtained in 48% yield and 87% enantiomeric excess.
In the next step, two other ligands (2b, 2c) were tested under the
optimized conditions (Table 2, entries 2 and 3). Compound 2c bear-
ing a cyclohexyl ring as the R group (Scheme 1) was the best ligand
Herein, we report the use of aziridine-2-semicarbazide-type
ligands which, in combination with Zn(II), are efficient catalysts
in asymmetric aldol reactions. It is worth mentioning that
semicarbazide ligands are almost unknown in the field of asym-
metric synthesis.
O
O
H
N
H
N
In a series of reports, methods for the synthesis and discussions
on the reactivity of diverse carbohydrazide derivatives were
NH2
RNCO
N
H
N
H
R
N
N
O
described.8–12 We also reported
a convenient synthesis of
Ph
Ph
Ph
Ph
Ph
Ph
semicarbazide ligands starting from N-triphenylmethyl-aziridine-
2-carbohydrazide 1.13 Carbohydrazide 1 reacts smoothly with
1
2a, R = t-Bu
2b, R = n-Bu
2c
, R = cyclohexyl
⇑
Corresponding author. Tel.: +48 426355767.
E-mail address: mrach14@wp.pl (M. Rachwalski).
Scheme 1. Reagent and conditions: CH2Cl2, rt, 1 h.
http://dx.doi.org/10.1016/j.tetlet.2014.02.131
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2374
A. M. Pieczonka et al. / Tetrahedron Letters 55 (2014) 2373–2375
Table 1
with nitro-substituted aryl aldehydes. The yields were better than
those obtained in the case of acetone. The best diastereomeric ratio
(86:14) was achieved in the case of 2,4-dinitrobenzaldehyde, but
we were unable to determine the enantiomeric excess of the iso-
lated product by HPLC.
Aldol reaction of acetone and p-nitrobenzaldehyde with 5 mol % of 2a under various
conditions
O
OH O
O
H
The diastero- and enantioselectivity of the presented reactions
is in agreement with the literature, where an anti-selective process
is the most common.14,15 However, a number of syn-selective
direct asymmetric aldol additions have also been reported.4,16
The application of Lewis acidic metal complexes (mimicking the
mode of action of type II aldolases) in solvents containing water
is still difficult.17 Zinc can act as an efficient Lewis acid, even in
the presence of water,18,19 so we assumed that our ligands in com-
bination with Zn(II) can create zinc-containing catalysts, which act
through the generation of a zinc enolate, as similarly described in
the literature.4,14–20 It should be mentioned that our ligands con-
tain, with the exception of an aziridinyl nitrogen atom which
should primarily coordinate a metal atom (strong effective com-
plexation of a zinc cation was described earlier21–23), five other
potential chelating centers. The proposal of any tentative mecha-
nistic model which could explain the interactions between the
substrate and catalysts seems to be rather premature and specula-
tive at this stage of our studies.
O2N
O2N
Entry
Co-catalyst
Solvent
Yield (%)
eea (%)
1
2
3
4
—
Acetone
Acetone
0
0
23
48
0
0
82
87
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Acetone/H2O 0.9:0.1
Acetone/H2O 2.9:0.1
a
Determined by HPLC on a Chiralpak OD-H column.
Table 2
Aldol reactions of acetone with various aromatic aldehydes using different ligands
O
OH O
O
H
R
R
In summary, little is known about the use of semicarbazide
derivatives as chiral catalysts in asymmetric synthesis. Compounds
having an aziridine ring and semicarbazide moiety proved to be
very effective ligands in Zn(II)-catalyzed aldol reactions of acetone
with nitrobenzaldehydes yielding products with up to 98% ee.24
The same catalytic system in reaction with hydroxyacetone affor-
ded adducts in moderate diastereoselectivity and poor enantiose-
lectivity. These ligands are interesting for further research in the
field of asymmetric catalysis.
Entry
Catalyst
R
Yield (%)
eea (%)
1
2
3
4
5
6
7
2a
2b
2c
2c
2c
2c
2c
4-NO2
4-NO2
4-NO2
4-CF3
H
48
32
58
0
0
50
67
87
84
91
0
0
61
98
2-NO2
2,4-diNO2
a
Determined by HPLC on a Chiralpak OD-H column.
References and notes
1. Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.; Panzer, M. Org. Lett.
2006, 8, 4687–4690.
2. Bulut, A.; Aslan, A.; Dogan, O. J. Org. Chem. 2008, 73, 7373–7375.
3. Braga, A. L.; Paixao, M. W.; Westermann, B.; Schneider, P. H.; Wessjohann, L. A.
J. Org. Chem. 2008, 73, 2879–2882.
Table 3
Aldol reactions of hydroxyacetone with aromatic aldehydes
4. Paradowska, J.; Pasternak, M.; Gut, B.; Gryzło, B.; Młynarski, J. J. Org. Chem.
O
OH O
2012, 77, 173–187.
O
H
5. Rachwalski, M.; Jarzyn´ ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24, 421–
425.
OH
´
´
´
6. Rachwalski, M.; Jarzynski, S.; Jasinski, M.; Lesniak, S. Tetrahedron: Asymmetry
2013, 24, 689–693.
OH
R
R
´
´
7. Rachwalski, M.; Lesniak, S.; Kiełbasinski, P. Tetrahedron: Asymmetry 2010, 21,
1890–1892.
Entry
R
Yield (%)
dra (anti:syn)
eea (%) anti:syn
1
2
3
4-NO2
2-NO2
2,4-diNO2
80
82
98
80:20
64:36
86:14
16:29
3:16
ndb
8. Pieczonka, A. M.; Mloston´ , G.; Heimgartner, H. Helv. Chim. Acta 2012, 95, 404–
414.
9. Pieczonka, A. M.; Mloston´ , G.; Heimgartner, H.; Linden, A. Helv. Chim. Acta 2012,
95, 1521–1530.
a
Determined by HPLC on a Chiralpak OD-H column.
Not determined.
10. Mloston´ , G.; Pieczonka, A. M.; Wróblewska, A.; Linden, A.; Heimgartner, H.
b
Tetrahedron: Asymmetry 2012, 23, 795–801.
11. Pieczonka, A. M.; Ciepielowski, K.; Cebulska, Z.; Mloston´ , G.; Linden, A.;
Heimgartner, H. Helv. Chim. Acta 2013, 96, 397–407.
´
12. Pieczonka, A. M.; Strzelczyk, A.; Sadowska, B.; Mloston, G.; Sta˛czek, P. Eur. J.
Med. Chem. 2013, 64, 389–395.
´
´
13. Lesniak, S.; Pieczonka, A. M.; Jarzynski, S.; Justyna, K.; Rachwalski, M.
Tetrahedron: Asymmetry 2013, 24, 1341–1344.
in the aldol reaction of acetone with p-nitrobenzaldehyde, so we
decided to test it in reactions with other aromatic aldehydes. Four
other aldehydes (Table 2, entries 4–7) were tested, but products
were only obtained in the reactions with nitro-substituted
compounds. The best result was achieved with 2,4-dinitrobenzal-
dehyde and the corresponding adduct was isolated in 67% yield
and 98% enantiomeric excess.
As these ligands were found to be efficient catalysts in Zn(II)-
mediated aldol reactions of acetone, we decided to extend our
research using hydroxyacetone as the carbonyl component
(Table 3). As the catalyst we used 5 mol % of compound 2c and
14. Paradowska, J.; Stodulski, M.; Młynarski, J. Adv. Synth. Catal. 2007, 349, 1041–
1046.
15. Daka, P.; Xu, Z.; Alexa, A.; Wang, H. Chem. Commun. 2011, 224–226.
16. Gu, Q.; Wang, X.-F.; Wang, L.; Wu, X.-Y.; Zhou, Q.-L. Tetrahedron: Asymmetry
2006, 17, 1537–1540.
17. Paradowska, J.; Stodulski, M.; Młynarski, J. Angew. Chem., Int. Ed. 2009, 48,
4288–4297.
18. Jankowska, J.; Młynarski, J. J. Org. Chem. 2006, 71, 1317–1321.
19. Jankowska, J.; Paradowska, J.; Rakiel, B.; Młynarski, J. J. Org. Chem. 2007, 72,
2228–2231.
20. Młynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502–1511.
21. Faure, R.; Loiseleur, H.; Bartnik, R.; Les´niak, S.; Laurent, A. Cryst. Struct.
Commun. 1981, 10, 515–519.
5 mol % of Zn(OTf)2 in
a mixture of hydroxyacetone/water
´
22. Bartnik, R.; Lesniak, S.; Laurent, A. Tetrahedron Lett. 1981, 4811–4812.
(2.9:0.1). All experiments were performed at room temperature
23. Bartnik, R.; Les´niak, S.; Laurent, A. J. Chem. Res. 1982, 287, 2701–2709.

A. M. Pieczonka et al. / Tetrahedron Letters 55 (2014) 2373–2375
2375
24. General procedure for the aldol reactions of acetone and hydroxyacetone with
aldehydes: The ketone (2.9 ml) and H2O (0.1 ml) were added to vial
products were in agreement with published data.4 3,4-Dihydroxy-4-(2,4-
dinitrophenyl)-butan-2-one (Table 3, entry 3).1H NMR (major): 7.99–7.98 (m,
1H); 7.88–7.86 (m, 1H); 7.51–7.48 (m, 1H); 5.53 (d, J = 2.4 Hz, 1H); 4.44 (d,
J = 2.4 Hz, 1H); 4.25 (br s, 1H), 3.59 (br s, 1H); 2.16 (s, 3H); 1H NMR (minor):
8.11–8.09 (m, 1H); 7.81–7.79 (m, 1H); 7.73–7.67 (m, 1H); 5.89 (br s, 1H); 4.55
(d, J = 2.4 Hz, 1H); 3.85 (br s, 1H); 2.18 (s, 3H). HRMS (CI): m/z [M+H]+ calcd for
a
containing the catalyst (0.025 mmol) and Zn(OTf)2 (0.025 mmol). After
vigorous stirring at rt for 15 min the aldehyde was added. The resulting
mixture was stirred at rt and monitored by TLC. Following completion, the
solvent was evaporated and the aldol product (anti/syn mixture) was purified
by flash column chromatography (hexane/EtOAc). Spectroscopic data of all
C10H11N2O7: 271.0561; found 271.0563.