Aziridinylethers as highly enantioselective ligands for the asymmetric addition of organozinc species to carbonyl compounds

Article abstract of DOI:10.1016/j.tetasy.2014.12.005

In the present paper a straightforward and efficient method for the synthesis of new chiral aziridinylether systems has been described. All of the new compounds have been tested in two stereocontrolled addition reactions of organozinc species to carbonyl compounds. The addition of diethyl- and phenylethynylzinc to aryl and alkyl aldehydes afforded the corresponding chiral products in high chemical yields (up to 90%) and with excellent ee's of approximately 93%.

Full text of DOI:10.1016/j.tetasy.2014.12.005

Tetrahedron: Asymmetry 26 (2015) 148–151
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Aziridinylethers as highly enantioselective ligands for the
asymmetric addition of organozinc species to carbonyl compounds
⇑
´
´
Adam M. Pieczonka, Stanisław Lesniak, Szymon Jarzynski, Michał Rachwalski
´
´
University of Łódz, Department of Organic and Applied Chemistry, Tamka 12, 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:
Received 24 November 2014
Accepted 10 December 2014
In the present paper a straightforward and efficient method for the synthesis of new chiral aziridinylether
systems has been described. All of the new compounds have been tested in two stereocontrolled addition
reactions of organozinc species to carbonyl compounds. The addition of diethyl- and phenylethynylzinc
to aryl and alkyl aldehydes afforded the corresponding chiral products in high chemical yields (up to 90%)
and with excellent ee’s of approximately 93%.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Nitrogen-containing chiral ligands are widely applied in asym-
metric catalysis,1,2 due to the coordination ability of the amine
function toward metal species, ranging from lithium and magne-
sium to zinc, copper, early transition metal complexes and also
precious metals. Among the various chiral nitrogen-bearing
ligands, amine alcohols constitute one of the most applicable and
effective groups of catalysts in asymmetric synthesis.3 It should
be stressed that in the literature reports concerning the use of chi-
ral amine-functionalized ligands in asymmetric synthesis, such
applications of amine ether derivatives are rarely reported on. In
addition to crown ethers with an amino function, which are used
in stereocontrolled reactions,4,5 the application of chiral, small
molecules of amine ethers has only been described randomly.6–9
On the other hand, chiral amine alcohols bearing an aziridine sub-
unit as an amino function have proven to be highly efficient cata-
lysts in asymmetric reactions in the presence of organozinc
compounds especially in reactions, such as the addition of diethyl-
and phenylethynylzinc to carbonyl compounds.10–18
2.1. Synthesis of ligands
A straightforward synthesis of the enantiopure ligands was car-
ried out in two steps. For the synthesis of aziridinylethers 4, an
inexpensive and readily available phenoxyacetyl chloride 1 acid
was used as the starting material. Thus, chloride 1 was treated with
the mixture of triethylamine and chiral aziridines 2a–c in diethyl
ether. The reactions were carried out at 0 °C, which allowed us to
obtain the corresponding amides 3a–c (Scheme 1) in very good
chemical yields of approximately 97% (Table 1).
Finally, reduction of amides 3a–c to the desired aziridinylethers
4 was performed by using triethoxysilane and zinc acetate follow-
ing the general protocol described by Beller et al.19 (Scheme 2).
R2
R1
R2
O
O
N
H
R1
, Et3N
O
O
Taking into account all of the aforementioned literature reports
we have decided to synthesize a series of new aziridinylether
ligands and to check their catalytic activity in the asymmetric addi-
tion of organozinc reagents to aldehydes.
Cl
N
Et2O, rt
1
3a-c
aziridines
Pri
Me
H
Pri
2a
(-)-(S)-2-methylaziridine
H
H
N
H
N
N
H
(-)-(S)-2-isopropylaziridine 2b
(+)-(R)-2-isopropylaziridine 2c
H
2c
2a
2b
⇑
Corresponding author.
E-mail address: mrach14@wp.pl (M. Rachwalski).
Scheme 1. Synthesis of amides 3a–c.
http://dx.doi.org/10.1016/j.tetasy.2014.12.005
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

A.M. Pieczonka et al. / Tetrahedron: Asymmetry 26 (2015) 148–151
149
Table 1
OH
Synthesis of amides 3a–c
ligand, Et2Zn
toluene
PhCHO
Ph
Ph
½ ꢀ
a 2D0
a
Entry
Amide
Yield (%)
5a
1
2
3
3a
3b
3c
98
97
98
+2.8
ꢁ0.6
+0.6
OH
Ph
ligand, Et2Zn
THF
PhCHO
Ph
+
a
In chloroform (c 1).
6a
Scheme 3. Asymmetric addition of diethyl- and phenylethynylzinc to
benzaldehyde.
R2
R2
O
R1
R1
1. (EtO)3SiH
Zn(OAc)2, THF
O
O
N
N
2. NaOH
3. Conclusion
3a-c
5a-c
Chiral ether-derived catalysts bearing one stereogenic center
located at the carbon atom of the aziridine moiety were found to
be efficient catalysts for the enantioselective addition of diethyl-
zinc and phenylethynylzinc to various aldehydes. The use of enan-
tiomeric ligands gave easy access to both enantiomeric addition
products.
Scheme 2. Reduction of amides 3a–c to form ligands 4a–c.
After aqueous NaOH work-up and purification by standard column
chromatography, ligands 4a–c were obtained as volatile oils. The
structures of all of the new chiral catalysts 4a–c were established
by using NMR and mass spectroscopy. Chemical yields and specific
rotation values of the final products 4a–c are summarized in
Table 2.
4. Experimental
4.1. General
1H and 13C NMR spectra were measured on a Bruker Avance III
instrument at 600 MHz using the solvent signals as reference.
Chemical shifts (d) are given in ppm and coupling constants J in
Hz. The assignments of the signals in 13C NMR spectra were made
on the basis of HMQC experiments. HR-MS: Bruker Esquire LC
spectrometers. Optical rotations were determined on a PERKIN–
ELMER 241 MC polarimeter with a sodium lamp at room temper-
ature (c 1). 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 (254 nm). The enan-
tiomeric excess values were determined by chiral HPLC (Knauer,
Chiralcel OD).
2.2. Screening of the ligands
In order to test the catalytic activity of the novel ligands 4a–c in
the asymmetric addition of organozinc reagents to aldehydes, the
reactions of diethylzinc and phenylethynylzinc with benzaldehyde
were chosen as the model transformations (Scheme 3). The results
are collected in Table 3.
From Table 3 it can be seen that all ligands 4a–c are prone to
catalyze the selected model transformations to give the desired
chiral products 5a and 6a in high chemical yields and with excel-
lent enantiomeric excess (up to 95%). Moreover, the use of enantio-
meric ligands 4b and 4c bearing moieties of both enantiomeric 2-
isopropylaziridine led to the formation of each enantiomer of
adducts 5a and 6a (Table 2, entries 2 and 3). Thus, each enantiomer
of the product may be obtained by using easily available enantio-
meric ligands. The absolute configurations of the stereogenic cen-
ters of 5a and 6a were attributed to the literature reports.10,20
4.2. Starting materials
All solvents and reagents are commercially available and were
used as received. The enantiomerically pure aziridines 2a–c were
prepared according to the literature.23
2.3. Asymmetric addition of diethylzinc and phenylethynylzinc
to various aldehydes catalyzed by ligand 4b
4.3. Synthesis of amides 3a–c
With the new ligands in hand, we decided to determine the
scope of the catalytic activity of the most active ligand 4b in the
aforementioned asymmetric addition reactions using a series of
aldehydes (Scheme 4). The results are summarized in Table 4.
All of the results obtained clearly indicate that the selected
ligand 4b could be considered as a highly efficient catalyst for
the asymmetric additions of diethylzinc and phenylethynylzinc
to aldehydes, leading to the formation of the desired alcohols in
high chemical yields and with high ee’s.
In a round-bottomed flask, aziridine 2 (1 mmol), triethylamine
(1 mmol), and diethyl ether (10 mL) were placed. The mixture
was cooled to 0 °C using an ice bath and chloride 1 (1 mmol) in
THF was added dropwise. After 30 min of stirring at room temper-
ature, the precipitate was filtered off and the filtrate was concen-
trated on a rotary evaporator to yield the corresponding amides
3a–c.
Amide 3a (colorless oil, 187 mg, 98%), 1H NMR (CDCl3): d = 1.34
(d, J = 5.5 Hz, 3H), 2.02 (d, J = 3.6 Hz, 1H), 2.45 (d, J = 5.8 Hz, 1H),
2.61–2.63 (m, 1H), 4.67 (d, J = 16.0 Hz, 1H), 4.71 (d, J = 16.0 Hz,
1H), 6.92–6.99 (m, 3H), 7.28–7.30 (m, 2H).
Amide 3b (colorless oil, 212 mg, 97%), 1H NMR (CDCl3): d = 0.96
(d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.65–1.70 (m, 1H), 2.12
(d, J = 3.7 Hz, 1H), 2.39–2.42 (m, 1H), 2.45 (d, J = 6.1 Hz, 1H), 4.71
(d, J = 15.7 Hz, 1H), 4.75 (d, J = 15.7 Hz, 1H), 6.94–7.02 (m, 3H),
7.30–7.34 (m, 2H).
Table 2
Synthesis of catalysts 4a–c
½ ꢀ
a 2D0
a
Entry
Compound
Yield (%)
1
2
3
4a
4b
4c
89
92
90
+4.0
ꢁ0.3
+0.3
Amide 3c (colorless oil, 215 mg, 98%), 1H NMR (CDCl3): d = 0.96
(d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.65–1.70 (m, 1H), 2.12
(d, J = 3.7 Hz, 1H), 2.39–2.42 (m, 1H), 2.45 (d, J = 6.1 Hz, 1H), 4.71
a
In chloroform (c 1).

150
A.M. Pieczonka et al. / Tetrahedron: Asymmetry 26 (2015) 148–151
Table 3
Screening of ligands 4a–c
Entry
Ligand
Product 5a
Product 6a
a
eeb (%)
Abs. config.c
Yield (%)
eeb (%)
Abs. config.c
½ ꢀ
a 2D0
a
Yield (%)
[a]
D
1
2
3
4a
4b
4c
90
96
94
ꢁ41.8
ꢁ43.6
+40.9
93
97
91
(S)
(S)
(R)
92
94
91
ꢁ4.6
ꢁ4.7
+4.4
91
93
88
(S)
(S)
(R)
a
b
c
In chloroform (c 1).
Determined using chiral HPLC.
According to literature data.10,20
OH
2.81 (m, 1H), 4.04–4.07 (m, 2H), 6.83–6.88 (m, 3H), 7.19–7.22
(m, 2H); 13C NMR (CDCl3): d = 19.6, 20.4 (2 CH3), 31.7 (CH2), 32.9
(CH), 46.3 (CH), 61.9, 71.4 (2 CH2), 112.4, 119.8, 128.4 (5 Car),
138.5 (Cq ar); HRMS (ES+): calcd for C13H19NO: 205.1545, found:
205.1545.
5b
Ligand , Et2Zn
RCHO
R
toluene
5a-e
Ligand 4c (colorless oil, 185 mg, 90%), 1H NMR (CDCl3): d = 0.86
(d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.13–1.18 (m, 1H), 2.26
(d, J = 6.0 Hz, 1H), 1.53–1.56 (m, 2H), 2.34–2.38 (m, 1H), 2.77–
2.81 (m, 1H), 4.04–4.07 (m, 2H), 6.83–6.88 (m, 3H), 7.19–7.22
(m, 2H); 13C NMR (CDCl3): d = 19.6, 20.4 (2 CH3), 31.7 (CH2), 32.9
(CH), 46.3 (CH), 61.9, 71.4 (2 CH2), 112.4, 119.8, 128.4 (5 Car),
138.5 (Cq ar); HRMS (ES+): calcd for C13H19NO: 205.1545, found:
205.1546.
5b
OH
R
Ligand , Et2Zn
Ph
RCHO
Ph
+
THF
6a-e
Scheme 4. Additions of diethyl- and phenylethynylzinc to aldehydes in the
presence of ligand 4b.
(d, J = 15.7 Hz, 1H), 4.75 (d, J = 15.7 Hz, 1H), 6.94–7.02 (m, 3H),
7.30–7.34 (m, 2H).
4.5. Asymmetric addition of diethylzinc to aldehydes: general
procedure10
4.4. Synthesis of ligands 4a–c
Chiral catalysts of type 4 (0.1 mmol) in dry toluene (5 mL) were
placed in a round-bottom flask. The mixture was cooled to 0 °C and
a solution of diethylzinc (1.0 M in hexane, 3.0 mmol) was added
under argon. After stirring for 30 min, the corresponding aldehyde
(1.0 mmol) was added at 0 °C, and the mixture was stirred at room
temperature overnight. Next, 5% HCl aqueous solution was added,
layers were separated and the aqueous phase was extracted with
diethyl ether (4 ꢂ 10 mL). The combined organic layers were
washed with brine (10 mL) and dried over anhydrous MgSO4. The
solvents were evaporated to afford the crude alcohols 5a–e, which
were purified via column chromatography on silica gel (hexane
with ethyl acetate in gradient). The yields, specific rotations, enan-
tiomeric excess values and the absolute configurations of products
5a–e are collected in Table 4. The spectroscopic data are in full
agreement with those reported in the literature.10,12,20,21
In a round-bottomed flask zinc acetate (1 mmol), triethoxysilane
(5.0 mmol), and freshly distilled dry THF (3 mL) were placed. The
mixture was stirred for 30 min under argon followed by the addition
of the corresponding amide 3 (1.0 mmol) in THF (2 mL). The mixture
was heated at reflux on an oil bath and after 6 h was cooled to room
temperature and treated with 1 M NaOH (10 mL). After 3 h of stir-
ring, the mixture was extracted with diethyl ether, and the com-
bined organic phases were dried over anhydrous Na2SO4, and
concentrated in vacuo using an ice bath to afford the crude products,
which after column chromatography (CH2Cl2) gave the final ligand
structures 4a–c. The chemical yields and specific rotation values of
ligands 4a–c are summarized in Table 2.
Ligand 4a (colorless oil, 157 mg, 89%), 1H NMR (CDCl3): d = 1.22
(d, J = 5.5 Hz, 3H), 1.38 (d, J = 6.3 Hz, 1H), 1.51–1.54 (m, 1H), 1.57
(d, J = 3.7 Hz, 1H), 2.63–2.72 (m, 2H), 4.14–4.19 (m, 2H), 6.94–
6.98 (m, 3H), 7.29–7.32 (m, 2H); 13C NMR (CDCl3): d = 18.2 (CH3),
34.2 (CH2), 35.0 (CH), 60.3, 69.2 (2 CH2), 112.8, 119.4, 128.2 (5
Car), 138.2 (Cq ar); HRMS (ES+): calcd for C11H15NO: 177.1232,
found: 177.1231.
4.6. Asymmetric addition of phenylethynylzinc to aldehydes—
general procedure12
To a solution of a ligand of type 4 (0.2 mmol) in THF (5 mL), was
added a solution of diethylzinc (1.4 mL, 1.4 mmol, 1.0 M in hexane)
at room temperature under argon. After the mixture was stirred at
Ligand 4b (colorless oil, 189 mg, 92%), 1H NMR (CDCl3): d = 0.86
(d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.13–1.18 (m, 1H), 2.26
(d, J = 6.0 Hz, 1H), 1.53–1.56 (m, 2H), 2.34–2.38 (m, 1H), 2.77–
ambient temperature for 30 min, phenylacetylene (154 lL,
Table 4
Additions of diethyl- and phenylethynylzinc to aldehydes in the presence of ligand 4b
Entry
R
Products 5a–e
Products 6a–e
eeb (%)
Abs. config.c
Yield (%)
eeb (%)
Abs. config.c
a
½ ꢀ
a 2D0
a
Yield (%)
[
a
]
D
1
2
3
4
5
Ph
96
92
88
91
89
ꢁ43.6
ꢁ46.5
+6.0
97
89
85
93
85
(S)
(S)
(S)
(S)
(S)
94
88
89
91
86
ꢁ4.7
ꢁ7.1
ꢁ3.1
+3.6
93
85
88
89
84
(S)
(R)
(S)
(R)
(R)
2-MeOC6H4
n-Pr
4-BrC6H4
2-MeC6H4
ꢁ8.1
ꢁ40.0
ꢁ10.4
a
b
c
In chloroform (c 1).
Determined using chiral HPLC.
According to literature data.10,12,21,22

A.M. Pieczonka et al. / Tetrahedron: Asymmetry 26 (2015) 148–151
151
6. Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y. Tetrahedron: Asymmetry 1995, 6,
2109–2112.
7. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1673–1679.
8. Shi, M.; Jiang, J.-K.; Feng, Y.-S. Tetrahedron: Asymmetry 2000, 11, 4923–4933.
9. Liu, Y.; Da, C.-S.; Yu, S.-L.; Yin, X.-G.; Wang, J.-R.; Fan, X.-Y.; Li, W.-P.; Wang, R. J.
Org. Chem. 2010, 75, 6869–6878.
1.4 mmol) was added, and stirring was continued for another
30 min. The solution was cooled to 0 °C (ice bath) and treated with
the corresponding aldehyde (1.0 mmol), after which the resulting
mixture was stirred for 2 h at 0 °C and then overnight at room tem-
perature. After completion of the reaction (TLC control), it was
quenched with 5% aqueous HCl. The resulting mixture was
extracted with diethyl ether (4 ꢂ 10 mL) and the combined organic
layers were washed with brine. After the organics were dried over
anhydrous MgSO4, the solvents were removed in vacuo. The resi-
due was purified by column chromatography (silica gel, hexane
with ethyl acetate in gradient) to afford the corresponding prod-
ucts 6a–e. The yields, specific rotations, enantiomeric excess val-
ues, and the absolute configurations of the products 6a–e are
collected in Table 4. The spectroscopic data are in full agreement
with those reported in the literature.10,12,20,21
´
´
10. Lesniak, S.; Rachwalski, M.; Sznajder, E.; Kiełbasinski, P. Tetrahedron:
Asymmetry 2009, 20, 2311–2314.
´
´
11. Rachwalski, M.; Lesniak, S.; Kiełbasinski, P. Tetrahedron: Asymmetry 2010, 21,
1890–1892.
12. Rachwalski, M.; Les´niak, S.; Kiełbasin´ ski, P. Tetrahedron: Asymmetry 2010, 21,
2687–2689.
13. Rachwalski, M.; Jarzyn´ ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24, 421–
425.
14. Rachwalski, M.; Jarzyn´ ski, S.; Jasin´ ski, M.; Les´niak, S. Tetrahedron: Asymmetry
2013, 24, 689–693.
15. Rachwalski, M.; Jarzyn´ ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24,
1117–1119.
´
´
16. Lesniak, S.; Rachwalski, M.; Jarzynski, S.; Obijalska, E. Tetrahedron: Asymmetry
2013, 24, 1336–1340.
17. Rachwalski, M. Tetrahedron: Asymmetry 2014, 25, 219–223.
18. Rachwalski, M.; Kaczmarczyk, S.; Les´niak, S.; Kiełbasin´ ski, P. ChemCatChem
2014, 6, 873–875.
References
19. Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132,
1770–1771.
20. Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin, M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.; Liu,
S.-Z.; Wang, M. Chem. Eur. J. 2009, 15, 3069–3071.
21. Zhang, C.-H.; Yan, S.-J.; Pan, S.-Q.; Huang, R.; Lin, J. Bull. Korean Chem. Soc. 2010,
31, 869–873.
22. Chen, Y.-J.; Lin, R.-X.; Chen, C. Tetrahedron: Asymmetry 2004, 15, 3561–3571.
23. Xu, J. Tetrahedron: Asymmetry 2002, 13, 1129–1134.
1. Scheffler, U.; Mahrwald, R. Chem. Eur. J. 2013, 19, 14346–14396.
2. Kizirian, J.-C. Chem. Rev. 2008, 108, 140–205.
3. Ojima, I. Catalytic Asymmetric Synthesis, 3rd ed.; John Wiley & Sons, 2010.
4. Pham, T. S.; Czirok, J. B.; Balázs, L.; Pál, K.; Kubinyi, M.; Bitter, I.; Jászay, Z.
Tetrahedron: Asymmetry 2011, 22, 480–486.
}
5. Rapi, Z.; Démuth, B.; Keglevich, G.; Grun, A.; Drahos, L.; Sóti, L.; Bakó, P.
Tetrahedron: Asymmetry 2014, 25, 141–147.