Highly enantioselective aza-Henry reaction promoted by amine-functionalized tridentate sulfinyl ligands

Article abstract of DOI:10.1016/j.tetasy.2011.05.006

Diastereomerically pure tridentate heteroorganic ligands containing hydroxyl, sulfinyl, and amino moieties as nucleophilic centers, capable of binding various organometallic reagents, have proven to be highly efficient catalysts in enantioselective aza-He

Full text of DOI:10.1016/j.tetasy.2011.05.006

Tetrahedron: Asymmetry 22 (2011) 1087–1089
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective aza-Henry reaction promoted
by amine-functionalized tridentate sulfinyl ligands
Michał Rachwalski , Stanisław Le s´ niak , Piotr Kiełbasi n´ ski b
a,
⇑
a
a
Department of Organic and Applied Chemistry, University of Łód ´z , Tamka 12, 91-403 Łód ´z , Poland
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łód ´z , Poland
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereomerically pure tridentate heteroorganic ligands containing hydroxyl, sulfinyl, and amino moie-
ties as nucleophilic centers, capable of binding various organometallic reagents, have proven to be highly
efficient catalysts in enantioselective aza-Henry reactions to give the desired products in very high yields
Received 27 April 2011
Accepted 12 May 2011
Available online 14 June 2011
(up to 98%) and with ees of up to 95%. The influence of the stereogenic centers, located on the sulfinyl
sulfur atom and in the amino moiety on the stereochemical course of the reaction is also discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
1
. Introduction
The asymmetric aza-Henry (or nitro-Mannich) reaction consti-
2. Results and discussion
2.1. Screening of the ligands
tutes as an attractive approach to access optically active precursors
of a broad range of various chiral building blocks.1 It consists of a
nucleophilic addition of nitroalkanes to imines and is a fundamen-
tal C–C bond forming reaction in organic synthesis.2 The impor-
tance of this transformation is illustrated by the considerable
development of the asymmetric version of the aza-Henry reac-
,2
Seven chiral tridentate ligands containing aziridines 1a–d,
(ꢀ)-(S)- and (+)-(R)-1-phenylethylamine 1e and 1f and (ꢀ)-(S)-
,3
0
1-(1 -naphthyl)-ethylamine 1g were applied, because the former
had given the best results in organozinc additions to various car-
bonyl compounds and the latter in the Henry additions, which
are closely related to the reaction being investigated herein
(Scheme 1).
To check the ability of these ligands to catalyze the enantiose-
lective aza-Henry reaction, we chose the addition of nitromethane
to benzaldehyde N-(tert-butoxycarbonyl)imine 2a as a reference
transformation. The reactions were performed under standard con-
ditions, but were different from those used for the Henry reaction
due to lack of a metal catalyst (Scheme 2). The results are shown in
Table 1.
1
–6
tion.
Some time ago, we elaborated upon the chemoenzymatic
synthesis of chiral tridentate ligands, bearing hydroxyl, sulfinyl,
and amine moieties with two stereogenic centers, one located on
the sulfinyl sulfur atom and the other on the carbon atom in the
7
amine moiety. These ligands proved to be very efficient catalysts
for various enantioselective reactions for asymmetric carbon–
carbon bond formation. Thus, the ligands bearing chiral acyclic
amine moieties turned out to be particularly useful for the stereo-
selective nitroaldol (Henry) reaction,8 while those bearing chiral
aziridinyl substituents were useful for the enantioselective dieth-
Inspection of Table 1 reveals that the stereogenic sulfinyl group
exerts a moderate asymmetric induction. This is visible in the case
of catalyst 1a bearing an achiral aziridine moiety (entry 1), in
which the sulfinyl group is the only source of chirality. Ligands
bearing chiral acyclic amines 1e–g proved to be much more effi-
cient catalysts (entries 5–7) than those obtained from chiral aziri-
dines 1b,c (entries 2 and 3). It should be noted that a similar
9
,10
ylzinc and phenylethynylzinc addition to aldehydes
and
1
1
enantioselective conjugate addition of diethylzinc to enones.
More-over, it was possible to obtain each enantiomer of the prod-
ucts of the aforementioned reactions using easily available, and
enantiopure, diastereomeric ligands.
With this in mind, we decided to broaden the applicability of
our tridentate ligands by using them as catalysts for the enantiose-
lective addition of nitromethane to imines, known as the
aza-Henry reaction.
8
relationship was found in the Henry reaction. Moreover, the reac-
tions catalyzed by two sets of diastereomeric catalysts 1b and 1c,
which were constructed from the opposite enantiomers of 2-iso-
propylaziridine, and 1e and 1f, constructed from opposite enantio-
mers of 1-phenylethylamine, led to the formation of the opposite
enantiomers of product 3. This means that the stereogenic center
located in the amine moiety exerts a crucial influence on the
stereochemistry of the reaction and hence on the absolute
⇑
Corresponding author.
E-mail address: mrach14@wp.pl (M. Rachwalski).
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.006

1
088
M. Rachwalski et al. / Tetrahedron: Asymmetry 22 (2011) 1087–1089
NR -R2
1
HO
O
S
1
Amines
H
H3C
NH2
H3C
NH2
Pri
Me
Me
H
Me
H
Pri
N
H
N
H
H
N
H
N
H
c
d
e, f
g
a
b
a) 2,2`-dimethylaziridine
b) (-)-(S)-2-isopropylaziridine
c) (+)-(R)-2-isopropylaziridine
d) (-)-(S)-2-methylaziridine
e) (-)-(S)-1-phenylethylamine
f) (+)-(R)-1-phenylethylamine
g) (-)-(S)-1-(1`-naphthyl)ethylamine
Scheme 1. Ligands for the asymmetric aza-Henry reaction.
Boc
Boc
Boc
Boc
N
N
HN
HN
NO2
NO2
Ligand, Et3N
MeNO2, toluene, -35 C
Ligand 1g, Et3N
o
o
MeNO , toluene, -35 C
2
R
R
2a
3
2
3
Scheme 2. Screening of ligands 1.
Scheme 3. The addition of nitromethane to various imines in the presence of ligand
g.
1
Table 1
Screening of ligands 1
Table 2
Addition of nitromethane to imines in the presence of 1g
Entry
Ligand
Product 3
Entry
R
Product 3
a
eeb (%)
Absolute configurationc
a
eeb
(%)
Yield (%)
[
a
]
D
Symbol Yield
%)
[a
]
D
Absolute
(
configurationc
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
52
84
86
76
93
91
97
ꢀ7.7
37
60
63
51
90
86
94
(R)
(R)
(S)
(R)
(R)
(S)
(R)
ꢀ12.6
+13.2
ꢀ10.7
ꢀ13.5
+12.9
ꢀ19.7
1
2
3
4
5
H
Me
MeO
NO
Br
a
b
c
d
e
97
97
98
91
95
ꢀ19.7 94
ꢀ35.0 96
ꢀ33.1 95
ꢀ15.2 86
ꢀ25.0 94
(R)
(R)
(R)
(R)
(R)
2
1g
a
b
c
In chloroform, c = 1.
a
b
c
In chloroform, c = 1.
Determined using chiral HPLC.
Taken from the literature.2
Determined using chiral HPLC.
2
Taken from literature.
effective catalysts for the title reaction, all leading to the appropri-
ate chiral b-nitroamine in high chemical yield with high enantio-
meric excesses. As mentioned above, each diastereomeric ligand
is easily accessible and leads to the formation of opposite enantio-
mer of the addition product. This means that the desired enantio-
mer of the product can be obtained by choosing the appropriate
enantiomeric amine to synthesize a diastereomeric ligand starting
configuration of the addition product. The small differences in the
ee values of the product may be explained in terms of ‘match’ and
‘
mismatch’ interactions with the stereogenic sulfinyl center.
2
.2. The addition of nitromethane to various imines in the
presence of catalyst 1e
7
from the same chiral precursor.
Having obtained the best results with ligand 1g, we then
decided to determine the scope of its activity. Thus ligand 1g
was used to catalyze the title transformation performed with a ser-
ies of imines (Scheme 3). The results are collected in Table 2.
The results shown in Tables 1 and 2 clearly indicate that ligand
3. Conclusions
The chiral tridentate ligands which contained two stereogenic
centers, one located on the sulfinyl sulfur atom and the other on
the carbon atom in the amine moiety, were found to be very
1
g as well as the two diastereomeric ligands 1e and 1f are very

M. Rachwalski et al. / Tetrahedron: Asymmetry 22 (2011) 1087–1089
1089
efficient catalysts for the enantioselective addition of nitromethane
to N-protected imines (aza-Henry or nitro-Mannich reaction). The
stereogenic centers located in the amine moieties exerted a decisive
influence on the stereochemistry of the reaction and the absolute
configuration of the products. Each enantiomer of the product
may be obtained by using easily available diastereomeric ligands.
5.32 (m, 1H), 7.18 (s, 4H). Other spectroscopic data of compound
3b are in agreement with those reported in the literature.2
4.2.3. tert-Butyl (R)-2-nitro-1-(4-methoxyphenyl)ethylcarbamate
3c
1
White solid, mp 133 °C. H NMR (CDCl
3
): d = 1.44 (s, 9H), 3.80 (s,
3
5
H), 4.66 (dd, J = 12.0, 5.4 Hz, 1H), 4.84 (br s, 1H), 5.17 (br s, 1H),
.30 (br s, 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H). Other
4
4
. Experimental
spectroscopic data of compound 3b are in agreement with those
reported in the literature.
2
.1. General
4
3
.2.4. tert-Butyl (R)-2-nitro-1-(4-nitrophenyl)ethylcarbamate
Unless otherwise specified, all reagents were purchased from
d
commercial suppliers and used without further purification. Tetra-
hydrofuran and toluene were distilled from sodium benzophenone
ketyl radical. NMR spectra were recorded on a Bruker instrument
1
Yellow solid, mp 133 °C. H NMR (CDCl
3
): d = 1.44 (s, 9H), 4.75
(
dd, J = 12.6, 4.6 Hz, 1H), 4.85 (m, 1H), 5.45 (m, 1H), 5.52 (br s,
1
H), 7.48 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.4 Hz, 2H). Other spectro-
3
at 600 MHz with CDCl as solvent and relative to TMS as internal
scopic data of compound 3b are in agreement with those reported
in the literature.
standard. Data are reported as s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, b = broad. Optical rotations were mea-
sured on a Perkin-Elmer 241 MC polarimeter with a sodium lamp
at room temperature (c 1). Melting points were measured on MEL-
TEMP apparatus and were uncorrected. Column chromatography
was carried out using Merck 60 Silica Gel. TLC was performed on
Merck 60 F254 silica gel plates. Visualization was accomplished
with UV light. The enantiomeric excess (ee) values were deter-
mined by chiral HPLC (Knauer, Chiralcel OD). Chiral tridentate li-
4
4
3
.2.5. tert-Butyl (R)-2-nitro-1-(4-bromophenyl)ethylcarbamate
e
White solid, mp 140 °C. 1H NMR (CDCl
): d = 1.45 (s, 9H), 4.51
3
(
(
m, 1H), 4.58 (m, 1H), 5.44 (m, 1H), 7.30 (d, J = 6.6 Hz, 2H), 7.54
d, J = 6.6 Hz, 2H). Other spectroscopic data of compound 3e are
2
in agreement with those reported in the literature.
7
gands were obtained using the procedure described previously.
Acknowledgment
Imines 2a–e were synthesized according to the protocols described
in the literature.1
2,13
Financial support provided by the Polish Ministry of Science
and Higher Education, Grant No:N N204 131140 (for PK) is grate-
fully acknowledged.
4
.2. General procedure for the asymmetric aza-Henry reaction2
A round-bottomed flask was charged with catalyst 1 (0.2 mmol)
and imine 2 (1 mmol). The solids were dissolved in dry toluene
References
(
(
4 mL) and the mixture was cooled to ꢀ35 °C. Nitromethane
1
.
Jiang, X.; Zhang, Y.; Wu, L.; Zhang, G.; Liu, X.; Zhang, H.; Fu, D.; Wang, R. Adv.
Synth. Catal. 2009, 351, 2096–2100.
10 mmol, 0.52 mL) was added and the mixture was stirred at this
temperature for 5 min. After this time, Et
3
N (0.4 mmol, 0.056 mL)
2. Rampalakos, C.; Wolff, W. D. Adv. Synth. Catal. 2008, 350, 1785–1790.
3.
Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62,
75–380.
was added, and the mixture was stirred at ꢀ35 °C for 8 h and then
at room temperature overnight. All the volatile components were
evaporated and the crude mixture was purified via column chro-
matography (hexane:ethyl acetate in gradient) to obtain optically
active products 3a–e. The yields, specific rotations and enantio-
meric excesses are collected in Tables 1 and 2.
3
4.
Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418–
3419.
5. Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625–627.
6.
Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc.
008, 130, 8606–8607.
2
7.
Rachwalski, M.; Kwiatkowska, M.; Drabowicz, J.; Kłos, M.; Wieczorek, W. M.;
Szyrej, M.; Siero n´ , L.; Kiełbasi n´ ski, P. Tetrahedron: Asymmetry 2008, 19, 2096–
2
101.
4
.2.1. tert-Butyl (R)-2-nitro-1-phenylethylcarbamate 3a
8
.
Rachwalski, M.; Le s´ niak, S.; Sznajder, E.; Kiełbasi n´ ski, P. Tetrahedron:
Asymmetry 2009, 20, 1547–1549.
1
White solid, mp 107 °C. H NMR (CDCl
dd, J = 12.0, 4.8 Hz, 1H), 4.85 (br s, 1H), 5.28 (br s, 1H), 5.38 (br
s, 1H), 7.30–7.41 (m, 5H). Other spectroscopic data of compound
3
): d = 1.44 (s, 9H), 4.70
(
9. Le s´ niak, S.; Rachwalski, M.; Sznajder, E.; Kiełbasi n´ ski, P. Tetrahedron:
Asymmetry 2009, 20, 2311–2314.
1
0. Rachwalski, M.; Le s´ niak, S.; Kiełbasi n´ ski, P. Tetrahedron: Asymmetry 2010, 21,
687–2689.
1. Rachwalski, M.; Le s´ niak, S.; Kiełbasi n´ ski, P. Tetrahedron: Asymmetry 2010, 21,
890–1892.
2
3
a are in agreement with those reported in the literature.
2
1
1
4
.2.2. tert-Butyl (R)-2-nitro-1-(4-methylphenyl)ethylcarbamate
1
1
2. Kanazawa, A. M.; Denis, J.; Greene, A. E. J. Org. Chem. 1994, 59, 1238–1240.
3. Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622–
2636.
3
b
1
White solid, mp 127 °C. H NMR (CDCl
3
): d = 1.44 (s, 9H), 2.34 (s,
3
H), 4.68 (dd, J = 12.6, 6.0 Hz, 1H), 4.83 (br s, 1H), 5.20 (br s, 1H),