Catalytic enantioselective addition of diethylzinc to aldehydes using aziridine based chiral ligands

Article abstract of DOI:10.1016/j.tetasy.2007.04.013

The readily available ferrocenyl substituted aziridinylmethanol 1 (FAM-1) was used as a chiral catalyst in the diethylzinc addition reaction to aromatic and aliphatic aldehydes to give secondary alcohols in high yields and up to 99% enantiomeric excess at room temperature. The catalyst can be recovered and used without losing its activity.

Full text of DOI:10.1016/j.tetasy.2007.04.013

Tetrahedron: Asymmetry 18 (2007) 1013–1016
Catalytic enantioselective addition of diethylzinc to aldehydes
using aziridine based chiral ligands
a
a
b
b,
*
¨
Adnan Bulut, Ayhan Aslan, Enver C¸ agrı Izg u¨ and Ozdemir Dogan
a
Department of Chemistry, Kırıkkale University, 71450 Kirikkale, Turkey
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b
Received 28 March 2007; accepted 12 April 2007
Abstract—The readily available ferrocenyl substituted aziridinylmethanol 1 (FAM-1) was used as a chiral catalyst in the diethylzinc addi-
tion reaction to aromatic and aliphatic aldehydes to give secondary alcohols in high yields and up to 99% enantiomeric excess at room
temperature. The catalyst can be recovered and used without losing its activity.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1
. Introduction
cient at low catalyst loading and at ambient temperature. It
is also desirable to have a catalyst that does not require
titanium isopropoxide used in more than 1 equiv.
1
0
Carbon–carbon bond forming reactions by the addition of
organometallic reagents to carbonyl compounds in the
presence of a chiral ligand are one of the most studied in
the field of asymmetric synthesis. In this sense, asymmetric
diethylzinc addition to prochiral aldehydes provides a gen-
eral method for the preparation of chiral secondary alco-
hols. After Oguni’s first work and Noyori’s discovery of
DAIB as an excellent catalyst in diethylzinc additions to
aldehydes, many catalysts have been reported in the litera-
ture. Chiral ligands with a ferrocenyl group in the struc-
We recently reported a new set of chiral FAM ligands 1–4,
ferrocenyl substituted aziridinylmethanols, for enantio-
selective asymmetric azomethine ylide cycloaddition reac-
tions. One of these ligands 2 produced pyrrolidines in up
1
2
11
to 95% ee. These ligands were also used in the enantio-
3
selective diethylzinc addition to enonones to obtain b-ethyl-
1
2
ated ketones in up to 80% ee. The performance of these
catalysts has also been tested in enantioselective diethylzinc
addition reactions to aldehydes. Herein, we report that
FAM-ligand 1 serves as an excellent catalyst for diethylzinc
additions to aldehydes.
4
ture have gained much attention in recent years and some
of these ligands have been tested in diethylzinc addition
1
d
reactions to aldehydes. There are also a number of recent
studies on the use of aziridine based chiral catalysts in
diethylzinc addition reactions to aldehydes. For example,
Tanner et al. have screened a number of aziridines includ-
2. Results and discussion
5
ing C-2 symmetric ones; Zwanenburg et al. have used
N-tritylaziridinyl(diphenyl)methanol and its polymer sup-
Chiral FAM-ligands 1–4 (Fig. 1) were synthesized by using
the literature procedure.
6
ported derivative; Wang et al. have used N-ferrocenyl-
11
7
methyl aziridino alcohols as chiral catalysts; Shi et al.
8
have used a C-2 symmetric aziridine as a catalyst; Finally,
First, the catalytic performances of these ligands were
tested in diethylzinc addition reactions starting with ligand
Page et al. studied aziridinylmethanols with different sub-
9
stituents on nitrogen. Although many chiral ligands have
1
(Table 1). Using p-anisidine and 15 mol % of this ligand
been synthesized to induce asymmetry in these reactions,
there is still a need to develop new chiral catalysts that
are (1) easy to obtain as both enantiomers and (2) are effi-
with 2 equiv of Et Zn at 0 ꢁC, 1-(4-methoxyphenyl)-1-pro-
2
panol was obtained in 98% yield and 92% ee after 14 h
reaction time. When the reaction was repeated with benzal-
dehyde under the same conditions, the product was
obtained with 89% yield and 96% ee. Next we determined
reaction conditions with regards to ligand loading and
*
Corresponding author. Tel.: +90 312 210 5134; fax: +90 312 210 3200;
e-mail: dogano@metu.edu.tr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.013

1014
A. Bulut et al. / Tetrahedron: Asymmetry 18 (2007) 1013–1016
Me
Me
Me
Me
H
H
H
H
H
Ph
Ph
Ph
Ph
R
N
R
N
R
N
R
N
OH
H
HO
OH
H
H
HO
S
H
R
H
S
R
H
R
R
S
S
Fe
Fe
Fe
H
Fe
1
2
3
4
Figure 1. Chiral Fam-ligand 1–4.
temperature using 1. When the reaction was carried out at
rt and 0.25 M concentration, the product was formed in
about the same yield and ee (99% and 92%, respectively)
after 5 h (entry 1). Upon lowering the ligand loading to
the aromatic ring in good to excellent yields (80–99%) and
the enantioselectivities (86–98%). The same ligand 1 is also
effective in enantioselective addition of diethylzinc to an
a,b-unsaturated aldehyde by forming the product in 96%
yield and 84% ee (entry 12). The catalytic effect of ligand
1 was also tested for aliphatic aldehydes. When heptanal
was used, enantioselective diethylzinc addition reaction
gave the product in 89% yield and 84% ee (entry 20). When
cyclohexanecarbaldehyde was used as the aldehyde, sec-
ondary alcohol was obtained in low yield (52%) but excel-
lent ee (94%, entry 22). Low yields for aliphatic aldehydes
3
mol % and increasing the concentration to 0.3 M, the
product was obtained in 93% yield and 90% ee at rt after
0 h (entry 2). Ligand 1 was also tested at 1 mol % but
1
the reaction was slow. As a result, 3 mol % ligand, rt,
and 10 h were determined as the standard set of reaction
conditions. Ligand 1 was then used in a series of diethylzinc
addition reactions to a standard set of aromatic, aliphatic,
and a,b-unsaturated aldehydes. The results of diethylzinc
addition to these aldehydes in the presence of chiral ligand
6
a,7b,10b
were also observed in previous studies.
Ligand 1 can
be recovered in more than 90% yield and used without los-
ing its activity (entries 3, 15, and 18). Using the same reac-
tion conditions, the catalytic performance of other ligands
2–4 was also tested. Ligands 2 and 3 were clearly inferior,
for example with p-anisidine yields were 42% and 53%, ee’s
were 39% and 26%, respectively (entries 4 and 5). Quasie-
1
are shown in Table 1.
As can be seen from the results, ligand 1 catalyzes the enan-
tioselective diethylzinc addition to aromatic aldehydes hav-
ing electron-donating and electron-withdrawing groups on
a
Table 1. Catalytic asymmetric diethylzinc addition to aldehydes
O
OH
*
1
(3 mol %)
+
Et Zn
2
R
H
R
toluene, rt, 10 h
b
c
d
Entry
aldehyde
Ligand
Yield (%)
ee (%)
Confign
e
1
2
3
4
5
6
7
8
9
p-MeOC
p-MeOC
p-MeOC
p-MeOC
p-MeOC
PhCHO
PhCHO
6
H
H
H
H
H
4
4
4
4
4
CHO
CHO
CHO
CHO
CHO
1
99
93
97
42
53
88
83
81
80
92
90
87
39
26
96
88
98
98
93
86
84
80
92
94
81
98
>99
88
84
82
94
R
R
R
R
S
6
6
6
6
1
f
1
2
3
1
4
1
1
1
1
1
4
1
R
S
p-CF
p-BrC
p-CNC
o-MeOC
3
C
6
H
4
CHO
CHO
CHO
CHO
R
R
R
R
R
S
6
H
4
10
11
12
13
14
15
16
17
18
19
20
21
22
6
H
4
>99
91
96
6
H
4
PhCH@CHCHO
PhCH@CHCHO
2-NaphthylCHO
2-NaphthylCHO
2-NaphthylCHO
FcCHO
85
>99
>99
98
88
93
80
89
85
52
R
R
S
f
1
4
1
R
R
S
f
FcCHO
FcCHO
1
4
1
4
1
g
g
n-C
n-C
6
H
H
13CHO
13CHO
R
S
6
c-C
6
H11CHO
R
a
b
c
d
e
f
All the reactions except for entry 1 were carried out at room temperature with 3 mol % catalyst loading.
Yields are isolated yields.
Determined by chiral HPLC except entry 10 which was based on the literature specific rotation value.
13
Determined by comparing with literature absolute optical rotation values.
5
mol % ligand loading.
The recovered ligand was used.
ee was determined by chiral HPLC using benzoate ester.
g

A. Bulut et al. / Tetrahedron: Asymmetry 18 (2007) 1013–1016
1015
nantiomeric14 ligand 4, on the other hand, gave the prod-
ucts in good yields and enantioselectivities (entries 7, 13,
and distilled over sodium prior to use. Products were puri-
fied by flash column chromatography on silica gel 60
(MERCK Co.) (230–400 mesh ASTM). TLC analyses were
performed on 250 lm Silica Gel 60 F254 plates and visual-
ized by quenching of UV fluorescence (kmax = 254 nm).
Optical rotations were measured by using a Rudolph Auto-
1
6, 19, and 21). In each case, the product was obtained with
an opposite configuration when compared to the product
obtained with ligand 1.
1
The stereogenic center on the aziridine ring plays the main
role in determining the configuration of the stereogenic cen-
ter of the product. Chiral ligands 1 and 2 with an (R)-config-
uration at aziridine center gave the products with an (R)-
configuration. Likewise, chiral ligands 3 and 4 with an (S)-
configuration at the aziridine center gave the products with
an (S)-configuration. These results are in line with the results
of the previous enantioselective diethylzinc addition reac-
tions carried out with aziridine based chiral ligands.
pol III polarimeter. H NMR samples were prepared in
CDCl –CCl (1:1 mixture) and recorded at 400 MHz on
3
4
Brucker Spectrospin Avance DPX-400 Ultra shield instru-
ment. The chemical shifts are reported in ppm downfield to
1
TMS (d = 0 ppm) for H NMR (7.26 ppm). Optical rota-
tion was obtained on a Perkin–Elmer 241 polarimeter.
Enantioselectivities were determined by HPLC analysis
and performed with a Dionex HPLC device equipped with
an P-680A pump, UVD 170U UV detector.
We propose the transition state in Figure 2 to account for
the stereoselectivity observed with chiral ligand 1. In this
transition state, the ethyl group is delivered from the re-
face of the aldehyde to give the product with an (R)-config-
uration. The R group of the aldehyde is farther away from
the bulky group on the ligand nitrogen.
4.2. Representative procedure for catalytic enantioselective
diethylzinc addition to aldehydes (Table 1, entry 6)
Diethylzinc (1.1 mL, 1 M solution in hexane) was added to
a stirred solution of chiral ligand (0.017 mmol, 560 lL used
from 0.03 M stock solution in toluene) in toluene (1.0 mL)
under Ar at room temperature. After stirring the resulting
reaction mixture at this temperature for 30 min, benzalde-
hyde (0.05 mL, 0.55 mmol) was added. Stirring was contin-
ued for 10 h at room temperature. At the end of this
period, the reaction mixture was diluted with EtOAc
(10 mL), quenched with a saturated aqueous solution of
Me
H
Ph
R *
N
H
Et
R
HO
H
H
Zn
Zn
* R
*
NH Cl (10 mL), and the two layers were separated. The
4
R
*
O
aqueous layer was extracted with EtOAc (2 · 10 mL).
O
S
R
Fc
The combined organic layers were dried over Na SO , con-
2
4
centrated and purified by flash column chromatography on
silica gel using 7:1 hexane/EtOAc. 1-Phenyl-1-propanol
was obtained in 88% yield (66 mg, 0.484 mmol). Chiral
HPLC was used to determine the ee.
Fc = ferrocenyl
Figure 2. Proposed TS for the reaction involving (R,R,S)-Fam 1 ligand.
3. Conclusion
4.2.1. 1-(4-Methoxyphenyl)-1-propanol (Table 1, entry 2).
(
Chiralcel OD-H column, 1.0 mL/min, 5% i-PrOH in hex-
In conclusion, we have developed a highly effective, new
chiral catalyst for the diethylzinc addition reactions to
aldehydes. Using 3 mol % of this chiral catalyst, secondary
alcohols can be obtained in up to 99% yields and 99% ee’s.
The sense of induction was found to be dependent on the
configuration of the aziridine ring. Thus both enantiomers
of the secondary alcohols can be obtained with the desired
ane); retention times: 13.64 min [major (R)-enantiomer]
20
and 16.10 min [minor (S)-enantiomer] ½aꢀ ¼ þ34:0 (c
D
1
5
2
.60 CHCl ) for (R)-enantiomer with ee = 90%. Lit.
3
24
½
aꢀ ¼ ꢁ28:3 (c 2.20, C H ) for (S)-enantiomer with
D
6
6
ee = 87%.
4
.2.2. 1-Phenyl-1-propanol (Table 1, entry 6). (Chiralcel
configuration by choosing the appropriate ligand. The
advantages of these catalysts are ease of preparation11 (pre-
OD column, 1.0 mL/min, 2% i-PrOH in hexane); retention
times: 19.35 min (major (R)-enantiomer) and 21.73 min
pared on a gram scale), efficiency at low catalyst loading,
and high enantioselectivities at ambient temperatures. An-
other advantage of these catalysts is that their antipodes
can be easily synthesized starting from (S)-methylbenzyl-
amine. The catalytic effect of these ligands for other asym-
metric reactions is currently under investigation in our
laboratory and will be reported in due course.
20
[
(
minor (S)-enantiomer] ½aꢀ ¼ þ30:2 (c 2.20, CHCl ) for
D
3
1
5
24
D
R)-enantiomer with ee = 96%. Lit.
.99, CHCl ) for (S)-enantiomer with ee = 81%.
½aꢀ ¼ ꢁ36:6 (c
0
3
4
.2.3. 1-(p-Trifluoromethylphenyl)-1-propanol (Table 1,
entry 8). (Chiralcel OJ-H column, 1.0 mL/min, 2% i-
PrOH in hexane); retention times: 17.97 min (major (R)-
enantiomer) and 16.40 min [minor (S)-enantiomer]
2
0
½
aꢀ ¼ þ18:6 (c 3.4, CHCl ) for (R)-enantiomer with
D
3
1
6
4. Experimental
ee = 98%. Lit. [a] = +19.5 (c 3.2, CH OH) for (R)-enan-
D
3
tiomer with ee = 78%.
4
.1. General
4.2.4. 1-(4-Bromophenyl)-1-propanol (Table 1, entry 9).
All of the reactions were performed in flame-dried glass-
ware under an atmosphere of argon. Toluene was dried
(Chiralcel OB column, 0.3 mL/min, 3% i-PrOH in hexane);
retention times: 33.19 min (major (R)-enantiomer) and

1016
A. Bulut et al. / Tetrahedron: Asymmetry 18 (2007) 1013–1016
2
9.18 min [minor (S)-enantiomer] [a] = +26.7 (c 1.50,
Middle East Technical University, and Kirikkale Univer-
sity Research Foundations for the financial support.
D
1
7
20
D
CHCl ) for (R)-enantiomer with ee = 98%. Lit. ½aꢀ
¼
3
þ15:8 (c 1.49, C H ) for (R)-enantiomer with ee = 90.3%.
6
6
4
.2.5. 1-(4-Cyanophenyl)-1-propanol (Table 1, entry 10).
References
2
0
½
aꢀ ¼ þ31:6 (c 0.5, CHCl ) for (R)-enantiomer with
D
3
1
3
23
D
1
. Reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int.
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Bryce, M. R. Tetrahedron: Asymmetry 2003, 14, 2297.
ee = 93%. Lit. ½aꢀ ¼ þ23:2 (c 11.0, CHCl ) for (R)-
3
enantiomer with ee = 69%.
4
(
.2.6. 1-(2-Methoxyphenyl)-1-propanol (Table 1, entry 11).
Chiralcel OD column, 0.5 mL/min, 3% i-PrOH in hexane);
retention times: 27.36 min [major (R)-enantiomer] and
2
3
20
2
4.77 min [minor (S)-enantiomer] ½aꢀ ¼ þ17:6 (c 4.1,
D
1
5
22
D
CHCl ) for (R)-enantiomer with ee = 86%. Lit. ½aꢀ
¼
3
ꢁ
36:0 (c 0.71, C H CH ) for (S)-enantiomer with
6 5 3
ee = 59%.
5
. Tanner, D.; Korno, H. T.; Gujarro, D.; Andersson, P. G.
Tetrahedron 1998, 54, 14213.
4
.2.7. (E)-1-Phenyl-1-penten-3-ol (Table 1, entry 12). (Chi-
ralcel OD column, 1.0 mL/min, 5% i-PrOH in hexane);
retention times: 13.65 min [major (R)-enantiomer] and
2
6
. (a) Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg, B.
Synlett 1999, 1571; (b) Holte, P.; Wijgergangs, J.-P.; Thijs, L.;
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(c) Shadakshari, U.; Nayak, S. K. Tetrahedron 2001, 57,
20
3.95 min [minor (S)-enantiomer] ½aꢀ ¼ þ4:3 (c 2.1,
D
1
5
24
D
CHCl ) for (R)-enantiomer with ee = 84%. Lit. ½aꢀ
¼
3
ꢁ
6:3 (c 1.73, CHCl ) for (S)-enantiomer with ee = 88%.
3
8
185.
4
.2.8. 1-(2-Naphthyl)-1-propanol (Table 1, entry 14). (Chi-
7. (a) Wang, M.-C.; Liu, L.-T.; Zhang, J.-S.; Shi, Y.-Y.;
Wang, D.-K. Tetrahedron: Asymmetry 2004, 15, 3853; (b)
Wang, M.-C.; Wang, D.-K.; Zhu, Y.; Liu, L.-T.; Guo, Y.-F.
Tetrahedron: Asymmetry 2004, 15, 1289; (c) Wang, M.-C.;
Hou, X.-H.; Xu, C.-L.; Liu, L.-T.; Li, G.-L.; Wang, D.-K.
Synthesis 2005, 3620; (d) Wang, M.-C.; Hou, X.-H.;
Chi, C.-X.; Tang, M.-S. Tetrahedron: Asymmetry 2006, 17,
ralcel OD column, 0.5 mL/min, 10% i-PrOH in hexane);
retention times: 27.72 min [major (R)-enantiomer] and
2
20
5.81 min (minor (S)-enantiomer) ½aꢀ ¼ þ35:1 (c 2.4,
D
1
5
24
D
CHCl ) for (R)-enantiomer with ee = 92%. Lit. ½aꢀ
¼
3
ꢁ
19:2 (c 1.79, C H ) for (S)-enantiomer with ee = 91%.
6 6
2
126.
4
.2.9. 1-Ferrocenyl-1-propanol (Table 1, entry 17). (Chi-
8
. Shi, M.; Jiang, J.-K.; Feng, Y.-S. Tetrahedron: Asymmetry
2000, 11, 4923.
ralcel OD column, 0.5 mL/min, 10% i-PrOH in hexane);
retention times: 13.67 min [major (R)-enantiomer] and
1
9. Page, P. C. B.; Allin, S. M.; Maddocks, S. J.; Elsegood, M. R.
J. J. Chem. Soc., Perkin Trans. 1 2002, 36, 2827.
10. Selected examples: (a) Blay, G.; Fernandez, I.; Marco-
Aleixandre, A.; Pedro, J. R. Tetrahedron: Asymmetry 2005,
20
4.55 min (minor (S)-enantiomer) ½aꢀ ¼ ꢁ66:5 (c 4.9,
D
1
8
20
D
CHCl ) for (R)-enantiomer with ee = 98%. Lit. ½aꢀ
¼
3
þ56 (c 1.4, C H ) for (S)-enantiomer with ee = 94%.
6
6
1
6, 1207; (b) Harada, T.; Kanda, K. Org. Lett. 2006, 8, 3817;
(
c) Hui, A.; Zhang, J.; Fan, J.; Wang, Z. Tetrahedron:
4
.2.10. 3-Nonanol (as benzoate) (Table 1, entry 20). (Chi-
Asymmetry 2006, 17, 2101.
ralcel OD-H column, 1.0 mL/min, hexane); retention
times: 15.20 min (major (R)-enantiomer) and 14.38 min
¨
1
1. Dogan, O.; Koyuncu, H.; Garner, P. P.; Bulut, A.; Youngs,
W.; Panzner, M. Org. Lett. 2006, 8, 4687.
12. Isleyen, A.; Dogan, O¨ . Tetrahedron: Asymmetry 2007, 18,
[
minor (S)-enantiomer].
6
79.
4
.2.11. 1-Cyclohexyl-1-propanol (as benzoate) (Table 1,
13. Williams, D. R.; Fromhold, M. G. Synlett 1997, 523.
1
1
1
1
4. Zhang, Q.; Curran, D. P. Chem. Eur. J. 2005, 11,
866.
5. Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9,
979.
6. Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry
002, 13, 1573.
entry 22). (Chiralpak AD column, 1.2 mL/min, 3% i-
PrOH in hexane); retention times: 11.44 min (major (R)-
enantiomer) and 12.61 min [minor (S)-enantiomer].
4
3
2
Acknowledgments
7. Guo, Q.-S.; Liu, B.; Lu, Y.-N.; Jiang, F.-Y.; Song, H.-B.; Li,
J.-S. Tetrahedron: Asymmetry 2005, 16, 3667.
The authors thank Scientific and Technical Research
Council of Turkey (TUBITAK, Grant No. 106T071), the
18. Arroyo, N.; Haslinger, U.; Mereiter, K.; Widhalm, M.
Tetrahedron: Asymmetry 2000, 11, 4207.