Enantioselective addition of diethylzinc to aldehydes in the presence of chiral aprotic ligands

Article abstract of DOI:10.1016/j.tetlet.2005.02.066

Optically active amino thiocyanate derivatives of (-)-norephedrine were found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes. This reaction provided optically active secondary alcohols with ee up to 96%.

Full text of DOI:10.1016/j.tetlet.2005.02.066

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2695–2696
Enantioselective addition of diethylzinc to aldehydes in the
presence of chiral aprotic ligands
*
Myung-Jong Jin, Young-Mok Kim and Kyoung-Soo Lee
School of Chemical Science & Engineering, Inha University, Inchon 402-751, Korea
Received 17 December 2004; revised 31 January 2005; accepted 4 February 2005
Abstract—Optically active amino thiocyanate derivatives of (ꢀ)-norephedrine were found to act as effective aprotic ligands for enan-
tioselective addition of diethylzinc to aldehydes. This reaction provided optically active secondary alcohols with ee up to 96%.
Ó 2005 Elsevier Ltd. All rights reserved.
Enantioselective addition of organozinc reagent to alde-
hyde in the presence of a catalytic amount of chiral
ligand has emerged as an attractive method for the
displacement with sodium thiocyanate (2.4 equiv) in
H O at 30 °C, respectively. This substitution proceeds
2
6
with retention of configuration. The presence of thiocy-
anate group in the compound 2 was confirmed by a
1
synthesis of optically active secondary alcohols. The
ꢀ1
enantioselectivity of this process is mainly dependent
on the chiral ligand, and therefore the search of new
ligands for the asymmetric catalysis is a field of continu-
ous interest. The catalysts used for the reaction have
been based on chiral protic ligands such as amino alco-
strong sharp infrared band at ꢁ2090 cm . In contrast,
isothiocyanate group shows a very broad band over the
region from 2200 cm to 2000 cm . The synthesis of
ꢀ1
ꢀ1 8
3a was also achieved by treatment of sodium thiometh-
oxide in THF instead of sodium thiocyanate in H O.
2
2
3
4
5
hols, diols, diamines and their derivatives, whereas
6
aprotic ligands have been scarcely studied in this area.
At first, the catalytic behaviour of the aprotic ligands 2
were examined in the addition of diethylzinc to benzalde-
a
9
Thus, it should be of interest to explore the catalytic
ability of aprotic ligands. Herein, we present new chiral
N,S-chelate aprotic ligands 2 and 3, together with their
catalytic applicability in the diethylzinc–aldehyde
addition.
hyde. Gratifyingly enough, the initial trial of the addi-
tion with 5 mol% of ligand 2a took place in excellent
enantioselectivity of 96% with remarkable reactivity
(Table 1, entry 1). The reaction was carried out in hexane
at rt for 3 h. Toluene or hexane–toluene gave rise to sli-
ghtly lower selectivity but with high conversions (entries
Me
Ph
Me
Ph
Me
Ph
2
and 3). Other aromatic aldehydes were also converted
to the corresponding (R)-secondary alcohols with high
optical purity in high yields. For an aliphatic aldehyde,
heptanal, good enantioselectivity was recorded (entry
12). Similar results were obtained from ligand 2b. It is
noteworthy that amino thiocyanates 2 give higher reac-
SR1
R N
OH
R N
SCN
Bu N
2
2
2
1
a,b
2a,b
3a,b
1
a: R = C H9
a: R = Ph
4
1
tion rate and better or comparable asymmetric induction
2a
b: R = (CH )
b: R = CH
2
2 5
3
than previously reported amino alcohols 1. This cata-
lytic system involving aprotic ligands 2 would not match
7
The amino thiocyanates 2a and b were readily prepared
in 80% yields by treatment of the corresponding (ꢀ)-N,N-
1
with the general mechanistic model of the diethylzinc–
2
a
aldehyde addition because the aprotic ligands do not
possess an acidic hydrogen atom. An unusual mecha-
nism may be operative in the addition. We assume that
simple coordination of nitrogen and sulfur atoms to
the zinc of diethylzinc generate an efficient chiral catalyst
4. Next we examined the use of amino sulfides 3 in the
addition of diethylzinc to benzaldehyde (entries 13 and
dialkylnorephedrines 1a and b with methanesulfonyl
chloride (1.0 equiv) and triethylamine (1.0 equiv) in
methylene chloride at ꢀ20 °C, followed by subsequent
*
Corresponding author. Tel.: +82 32 860 7469; fax: +82 32 872
959; e-mail: mjjin@inha.ac.kr
0
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.066

2696
M.-J. Jin et al. / Tetrahedron Letters 46 (2005) 2695–2696
R
N
References and notes
Me
CN
1. For reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49–69; (b) Soai, K.; Niwa, S. Chem.
Rev. 1992, 92, 833–856.
R
Ph
Et
Zn
Et
S
2. (a) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem.
1
991, 56, 4264; (b) Paleo, M. R.; Cabeza, I.; Sardina, J. J.
4
Org. Chem. 2000, 65, 2108–2113; (c) Dangel, B. D.; Polt, R.
Org. Lett. 2000, 2, 3003–3006; (d) Superchi, S.; Mecca, T.;
Giorgio, E.; Rosini, C. Tetrahedron: Asymmetry 2001, 12,
1235–1239; (e) Priego, J.; Mancheno, O. G.; Cabrera, S.;
Carretero, J. C. J. Org. Chem. 2002, 67, 1346–1353; (f)
Fontes, M.; Verdaguer, X.; Sola, L.; Pericas, M.; Riera, A.
J. Org. Chem. 2004, 69, 2532–2543.
. (a) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585–589; (b) Heckel, A.;
Seebach, D. Angew. Chem., Int. Ed. 2000, 39, 163–
165.
. (a) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1991,
28, 2717–2720; (b) Conti, S.; Falorni, M.; Giacomelli, G.;
Soccolini, F. Tetrahedron 1992, 48, 8993–8999.
5. (a) Katsuji, I.; Kimula, Y.; Okamura, H.; Katsuki, T.
Synlett 1992, 573–574; (b) Qiu, J.; Guo, C.; Zhang, X. J.
Org. Chem. 1997, 62, 2665–2668; (c) Yus, M.; Ramon, D.
J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103–
1104.
Table 1. Enantioselective addition of diethylzinc to aldehydes with
a
chiral aprotic ligands 2 and 3
OH
(R)
3
4
Ligand (5 mol%)
RT
RCHO + Et Zn
2
Et
R
H
b
Ligand Time (h) Yield (%) ee (%)
c
Entry
1
R
Ph
Ph
Ph
Ph
2a
2a
2a
2b
2a
2b
2a
2b
2a
2b
2a
2a
3a
3b
3
3
98
96
94
95
97
96
96
91
95
92
95
82
85
70
96
92
90
95
95
93
90
90
91
90
93
75
41
3
d
2
e
3
3
4
5
6
7
8
9
3
p-Cl-C
p-Cl-C
6
H
H
4
4
6
6
6
6
3
6
3
o-MeO-C
o-MeO-C
p-MeO-C
p-MeO-C
H
4
H
4
H
4
H
4
9
9
6. (a) Jin, M.-J.; Ahn, S.-J.; Lee, K.-S. Tetrahedron Lett. 1996,
37, 8767–8770; (b) Dieter, R. K.; Deo, N.; Lagu, B.; Dieter,
J. W. J. Org. Chem. 1992, 57, 1663–1671.
9
10
11
12
13
14
9
1
2-Naphthyl
C
6
7. For compound 2a: H NMR (CDCl
7.20 (m, 5H), 4.81 (d, J = 5.7 Hz, 1H), 3.05 (m, 1H), 2.52–
, 250 MHz) d 7.40–
3
6
H
13
6
Ph
Ph
12
18
2.34 (m, 4H), 1.40–1.06 (m, 8H), 1.08 (d, J = 6.7 Hz, 3H),
1
0.84 (t, J = 6.9 Hz, 6H); C NMR (CDCl
3
3
, 62.9 MHz) d
a
10.7, 14.0, 20.3, 30.9, 49.9, 62.0, 63.9, 128.3, 129.0, 126.3,
2
Reactions were carried out in hexane using 2.0 equiv of Et Zn unless
ꢀ1
20
1
MS (CI) m/z 305 (MH ).
31.5, 138.5; IR mSCN 2091 cm ; ½aꢂD ꢀ13.8 (c 1.0, CHCl3);
otherwise noted. Absolute configuration was assigned by the sign of
the optical rotation and elution order from a chiral OD column.
Measured as % conversion into product by GC.
+
1
For compound 2b: H NMR (CDCl
7.19 (m, 5H), 4.92 (d, J = 3.8 Hz, 1H), 2.83 (m, 1H), 2.51
b
c
3
, 250 MHz) d 7.35–
Determined by HPLC analysis (chiralcel OD column) or GC analysis
(
3H); C NMR (CDCl
m, 4H), 1.51 (m, 4H), 1.40 (m, 2H), 1.03 (d, J = 6.8 Hz,
(DEX chiral column).
Reaction in toluene.
Reaction in hexane–toluene, 1:1.
1
3
d
e
3
, 62.9 MHz) d 10.6, 24.7, 26.5, 50.6,
62.4, 67.0, 126.1, 127.7, 128.4, 132.5, 138.2; IR mSCN
ꢀ
1
20
2
(
089 cm ; ½aꢂD ꢀ42.5 (c 1.0, CHCl
3
); MS (CI) m/z 261
+
MH ).
1
4). The reaction proceeded smoothly and poor ee was
8
. Fresenius, W.; Huber, J. F. K.; Pungor, E.; Rechnitz, G. A.;
Simon, W.; West, T. S. Tables of Spectral Data for
Structure Determination of Organic Compounds; Springer:
Berlin, 1989.
9. A typical procedure for the present catalytic reaction is
described as follows: benzaldehyde (106 mg, 1.0 mmol) was
added to a solution of amino thiocyanate 2a (15 mg,
observed. Interestingly, the amino thiocyanates led to
fast reaction with high ee, whereas the amino sulfides
dramatically decrease the enantioselectivity. This fact
suggests that the enantioselectivity strongly depends on
the electronic environment around the sulfur atom. In
conclusion, we have demonstrated that new chiral apro-
tic amino thiocyanates catalyze efficiently the enantio-
selective addition of dialkylzinc to aldehydes. Our study
may open the way to the use of aprotic ligands in the
dialkylzinc–aldehyde addition.
0
1
.05 mmol) in hexane (1.6 mL) at 0 °C. Diethylzinc (2 mL,
.0 M in hexane) was then added dropwise. The mixture
was allowed to warm to room temperature. The mixture
was stirred for an additional 3 h, observing the progress of
the reaction by GC. The reaction was quenched by the
addition of dilute aqueous NH
was extracted with CH Cl . The organic extract was dried
over anhydrous MgSO4 and evaporated under reduced
pressure. The residue was purified by flash chromatography
on silica gel. The ee was determined by HPLC with a Daicel
OD-H column.
4
Cl and the resulting mixture
2
2
Acknowledgments
This work was supported by Inha University Research
grant (INHA-2005).