Design, synthesis, and application of novel chiral ONN ligands for asymmetric alkylation

Article abstract of DOI:10.1007/s00706-012-0900-8

Starting from easily available chiral pool amino alcohols, a set of novel chiral ONN ligands was synthesized and their catalytic potential was examined in asymmetric alkylation. Ligands with a secondary central NH group and N-methylated ONN ligands were successfully applied as catalysts in the addition of diethyl zinc to various aromatic aldehydes, yielding secondary alcohols in excellent yields of up to 99 % ee.

Full text of DOI:10.1007/s00706-012-0900-8

Monatsh Chem
DOI 10.1007/s00706-012-0900-8
ORIGINAL PAPER
Design, synthesis, and application of novel chiral ONN ligands
for asymmetric alkylation
•
•
•
Katharina Bica Sonja Leder Kurt Mereiter
Peter Gaertner
Received: 5 November 2012 / Accepted: 4 December 2012
Ó Springer-Verlag Wien 2013
Abstract Starting from easily available chiral pool amino
alcohols, a set of novel chiral ONN ligands was synthe-
sized and their catalytic potential was examined in
asymmetric alkylation. Ligands with a secondary central
NH group and N-methylated ONN ligands were success-
fully applied as catalysts in the addition of diethyl zinc to
various aromatic aldehydes, yielding secondary alcohols in
excellent yields of up to 99 % ee.
great interest in this type of reaction [3, 4]. Since the initial
report from Oguni and Noyori of their discovery of (2S)-
exo-(dimethylamino)isoborneol (DAIB), which is an
excellent catalyst in the asymmetric diethyl zinc alkylation
of aldehydes, this C–C bond-forming reaction has been
greatly refined over the last few decades ([5–7]; for a
review, see [8]). Ligands with two coordinating heteroat-
oms are widely used as catalysts, and b-amino alcohols are
among the best catalysts, allowing diethyl zinc alkylation
in good yields and with high enantiomeric excesses [9].
The aim of our work was to design and synthesize ligands
that possess three different nucleophilic centers capable of
binding organometallic reagents. Such ONN ligands could
potentially play an important role in C–C bond-forming
reactions, as they have a third site that can coordinate to the
metal atom, in contrast to amino alcohols [10, 11]. The
behavior of these tridentate ONN ligands is rather difficult
to predict in comparison to their parent NO ligands; they
may conserve [12], enhance [13], or even reverse [14]
selectivity, or decrease the enantiomeric excess [15]. The
few examples of diethyl zinc alkylation catalyzed by tri-
dentate ligands reported in the literature tend to be
polymer-supported reactions, or afford the alkylated
product in low enantiomeric excess [16–19]. Therefore,
new easily accessible and effective chiral ligands for use in
a variety of asymmetric reactions are still desirable.
Keywords Chirality Á Asymmetric synthesis Á Ligands Á
Diethyl zinc Á Organometallic compounds Á Amino alcohols
Introduction
Pioneering work by Oguni and Omi provided the starting
point for numerous improvements in the enantioselective
synthesis of optically active alcohols for use as chiral
building blocks and intermediates in the preparation of
biologically active compounds [1, 2]. The successful
application of diamino alcohols as ligands in organolithium
additions by Mukayama, as well as Sato’s work on the
addition of diethyl magnesium to aldehydes, has aroused
K. Bica (&) Á S. Leder Á P. Gaertner (&)
Institute of Applied Synthetic Chemistry, Vienna University
of Technology, Getreidemarkt 9/163,
1060 Vienna, Austria
Starting from chiral pool derived amino alcohols, we
developed a straightforward synthetic protocol for a new
type of chiral ONN ligand that can be applied in general to
any primary or secondary amino alcohol. The introduction
of a third nitrogen functionality in close proximity to the 1,2-
amino alcohol functionality provides an additional possible
coordination site, and thus three different nucleophilic
centers within a distance of 3–4 bond lengths are available
for direct interactions with metals or substrates (Fig. 1).
e-mail: kbica@ioc.tuwien.ac.at
P. Gaertner
e-mail: peter.gaertner@tuwien.ac.at
K. Mereiter
Institute for Chemical Technologies and Analytics,
Vienna University of Technology,
Vienna, Austria
123

K. Bica et al.
performed (Scheme 1). Reaction in the presence of a freshly
activated molecular sieve in anhydrous methanol gave a
complex and inseparable mixture of two isomeric imines and
the N,O-acetal, which was reduced directly with sodium
borohydride to yield the secondary amino alcohols 7, 8, 9, 10,
and 11 as the sole products. In order to obtain satisfactory
yields, it was necessary to use an exact stoichiometric amount
of freshly distilled pyridine-3-carboxaldehyde; otherwise, it
was difficult to separate out the resulting by-product pyridin-
3-ylmethanol.
Fig. 1 Scheme for a chelating chiral ligand with three centers for
coordination with a metal ion
While the products obtained already qualify as chiral
ligands, the presence of a secondary central nitrogen may
limit the application of these ligands, particularly in reac-
tions with strong nucleophiles [22]. Therefore, further
N-methylation was implemented using classical Leuckart–
Wallach conditions (HCHO/HCO2H), giving the methyl-
ated ONN ligands 13, 14, 15, 16, and 17 in just two steps
with a good overall yield. This general procedure employed
for the primary amino alcohols 1–5 was slightly adapted
for the secondary amino alcohol (S)-prolinol (6). (S)-Pro-
linol was simply refluxed with equimolar amounts of
pyridine-3-carboxaldehyde in acetonitrile without further
activation to give the cyclic N,O-acetal, which was then
reduced with sodium borohydride to yield the corre-
sponding ligand 12 in one step only.
Herein, we report the synthesis and characterization of
several new ONN ligands, as well as the first results and
enantioselectivities achieved using these ligands in the
asymmetric diethyl zinc alkylation of various aromatic
aldehydes.
Results and discussion
We chose a set of commercially available chiral 1,2-amino
alcohols from the chiral pool that have previously been
used for asymmetric reactions, including amino acid
derived alcohols, ephedrine, and the camphor derivative
2-aminoisoborneol [20, 21].
In a first step, reductive amination of the enantiopure
amino alcohol with pyridine-3-carboxaldehyde was
While the ligands 14, 15, 16, and 12 were obtained as light
yellow oils, we were able to crystallize the phenylalanine
N
N
OH
OH
OH
H
MS, NaBH4
NH2
HCHO
N
N
O
MeOH
HCOOH
89%
N
94%
1
7
13
N
N
H
MS, NaBH4
HCHO
NH2
OH
O
O
N
N
OH
OH
MeOH
85%
N
N
HCOOH
82%
2
8
14
OH
N
N
OH
OH
H
N
HCHO
MS, NaBH4
NH2
N
HCOOH
56-97%
MeOH
66-93%
R
R
R
15: R = i-Pr
16: R = s-Bu
17: R = Bn
9: R = i-Pr
10: R = s-Bu,
11: R = Bn
3: R = i-Pr
4: R = s-Bu
5: R = Bn
NaBH4
O
N
N
OH
OH
N
H
CH3CN
93%
N
6
12
Scheme 1
123

Design, synthesis, and application of novel chiral ONN ligands
derivative 11 and the ephedrine derivative 13. Single crystals
of 13 were grown from n-hexane/ethyl acetate, and the
anticipated structure of 13 was confirmed by single-crystal
X-ray analysis. The analysis revealed bond lengths between
the three heteroatoms that should allow multiple tethering to
metal cations (Fig. 2). The packing structure is dominated by
an intermolecular hydrogen bond between the pyridine
nitrogen and a face-to-face arrangement of pyridine and
benzyl ring systems.
was left to stir at room temperature for 24 h. Hydrolysis
followed by standard extractive work-up gave 1-phenyl-1-
propanol (19), which was further analyzed via chiral HPLC
after chromatographic purification.
All ligands with a secondary central NH group (7, 8, 9,
10, and 11) that were initially screened were able to cata-
lyze the reaction, but only poor enantioselectivities were
observed (Table 1, entries 1–5). Although excellent yields
were obtained, the best enantioselectivity was a rather
modest value of 45 % ee, obtained using the ephedrine
derivative 7 as catalyst (entry 1). The camphor-derived
(-)-DAIB analog 8 and the phenylalanine derivative 11
completely failed to induce selectivity (entries 2, 5). A
change of solvent did not improve enantioselectivity; on
the contrary, when n-hexane was used as solvent instead of
toluene, the yield dropped to just 59 %. This disappointing
selectivity compared to well-known ligands such as
N-methylephedrine or (-)-DAIB [8, 27, 28] suggested that
the formation of a conformationally rigid aggregate was
prevented by the presence of a secondary amine.
To examine the catalytic potential of these ligands, we
investigated the enantioselective alkylation of benzalde-
hyde (18) with diethyl zinc (Scheme 2). This catalytic
enantioselective addition of organometallic reagents to a
carbonyl group is one of the most powerful methods for the
preparation of chiral secondary alcohols and has therefore
been studied extensively [8, 11, 17, 23, 24]. The utilization
of several metal organyls in combination with a large
number of chiral ligands has been reported, making this
strategy superior to the comparable enantioselective
reduction of ketones [25, 26].
A catalytic amount of ligand (10 mol%) was reacted
with a 1 M solution of diethyl zinc in n-hexane at 0 °C.
Freshly distilled benzaldehyde was added and the reaction
Indeed, the N-methylation was observed to have a dra-
matic influence, with the selectivity increasing to 13 % ee for
the N-methylated phenylalanine-derived ligand 17 (entry 11)
and to 77 % ee for the N-methylated ephedrine derivative 13
(entry 7). Even better, almost complete enantioselectivity
was obtained with the exo-aminoisoborneol-derived ligand
14 (entry 8), which completely failed before N-methylation
(entry 2). However, the (S)-prolinol-derived ligand 12 failed
even though a tertiary amine structure is present (entry 6). No
Table 1 Asymmetric addition of diethyl zinc to benzaldehyde (18)
catalyzed by tridentate ligands
Entrya
Ligand
Yieldb 19/%
eec/%
45 (S)
1
7
94
85
2
8
1 (S)
16 (R)
16 (R)
1 (S)
3
9
93
4
10
11
12
13
14
15
16
17
84
5
95
6
93
2 (R)
7
79
77 (S)
[99 (S)
14 (R)
25 (S)
13 (S)
8
94
9
99
Fig. 2 Molecular structure of ephedrine derivative 13
10
11
a
84
[99
O
OH
10 mol% ligand
toluene, 0 °C
All reactions were performed with 2 mmol benzaldehyde,
4.4 mmol of a 1 M solution of Et2Zn in n-hexane, and 0.2 mmol
ligand at 0 °C for 24 h in toluene
∗
Et2Zn
b
Isolated yield of 19 after flash column chromatography
c
18
Scheme 2
19
Determined by HPLC using a Daicel (Tokyo, Japan) Chiralcel
OD-H column. Absolute configuration was determined by optical
rotation and comparison with literature values [8, 11, 17, 23, 24]
123

K. Bica et al.
significant improvement in N-methylation was noticed for
leucinol and valinol derivatives. Surprisingly, a reversal of
selectivity was observed in the case of the (S)-leucinol
derivative 10, which induced the (R)-enriched product rather
than the (S)-enriched alcohol derived from ligand 16 (entry 4
vs. 10), suggesting a fundamentally different transition state
for these tridentate ligands with a central secondary amine
group. Even though they are quite similar in structure, this
effect was not observed with the (S)-valinol derivatives 9 and
15. In this case, N-methylation led to a slight decrease in
selectivity but yielded a product with the same configuration
as the ligand 7 (entry 3 vs. 9).
bearing a benzene ring instead of a pyridine ring system.
For example, when the 3-pyridyl group of ONN ligand 14
is replaced with a benzene ring to obtain a comparable
bidentate system, the selectivity decreased only slightly,
from [99 % ee to 95 % ee, thus indicating that a compa-
rable transition state involving coordination with the
central tertiary amino group might be present [29].
Conclusion
We have prepared a set of efficient ONN chiral ligands for
the enantioselective addition of diethyl zinc to aldehydes.
These ligands are not only easily prepared, but they permit
high enantioselectivities of up to 99 % ee to be achieved
with various aromatic aldehydes at moderate temperatures
and a catalyst loading of 10 mol%. We anticipate that these
ligands will be applicable to a wide range of asymmetric
reactions, and more research in this direction is ongoing.
Considering these results, the presence of a central ter-
tiary amine in an ONN ligand appears to play a significant
role in controlling chiral induction during asymmetric
diethyl zinc addition. This is surprising, given that an
opposite effect is reported for the asymmetric Strecker
reaction, where N-methylated N-salicyl b-amino alcohol
fails and the free NH group appears to control enantiose-
lectivity [6].
Encouraged by these early results, the scope of the
reaction was expanded to a series of different aldehydes,
which were alkylated using a similar procedure in the
presence of catalyst 14 that gave the best selectivities of all
of the ligands investigated previously. The results, which
are summarized in Table 2, suggest efficient coordination
and activation of diethyl zinc, and prove the efficiency of
ligand 14, since the appropriate products were obtained in
high yields and with good to excellent selectivities ranging
from 64 to [99 % ee (Table 2).
Experimental
Commercially available reagents and solvents were used as
received from the supplier unless otherwise specified.
Diethyl ether, light petrol (60–80 °C fraction), ethyl ace-
tate, and dichloromethane were distilled prior to use.
Anhydrous toluene was predried over KOH and distilled
from Na/benzophenone. Anhydrous methanol was distilled
from magnesium turnings and stored over a molecular
sieve. 1H and 13C NMR spectra were recorded on a Bruker
(Ettlingen, Germany) DPX 200 at 200 and 50 MHz or on a
Bruker DRX 400 at 400 and 100 MHz, respectively, using
the solvent peak or TMS as reference. 13C NMR spectra
were run in proton-decoupled mode. Multiplicities are
referred to as s (singlet), d (doublet), t (triplet), q (quartet),
quin (quintet), sext (sextet), sept (septet), and m (multi-
plet). TLC analysis was done with precoated aluminum-
backed plates (silica gel 60 F254, Merck, Darmstadt,
Germany). Compounds were visualized by spraying with
5 % phosphomolybdic acid hydrate in ethanol and heating.
Vacuum flash chromatography (VFC) was carried out with
Merck 60 silica gel. Melting points of crystalline com-
pounds were determined with a Kofler hot-stage apparatus.
Specific rotations were measured on a PerkinElmer
(Waltham, MA, USA) 241 polarimeter. Elemental analysis
was carried out at the Laboratory for Microanalysis,
Department of Physicochemistry, Vienna University
The activity of tridentate ONN chiral ligands appears to
be comparable to that of the related bidentate ON ligands
Table 2 Diethyl zinc alkylation with various aromatic aldehydes
Entrya
Aldehyde
Yieldb/%
eec/%
1
2
3
4
5
6
7
8
9
10
a
4-Tolylaldehyde
86
71
98
[99
96
2-Tolylaldehyde
3-Tolylaldehyde
87
4-i-Pr-benzaldehyde
Pyridine-3-carboxaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
2-Chlorobenzaldehyde
1-Naphthaldehyde
91
97
[99
[99
86
64
[99
93
84
[99
88
85
Cinnamic aldehyde
43
22
All reactions were performed with 2 mmol aldehyde, 4.4 mmol of a
1 M solution of Et2Zn in n-hexane, and 0.2 mmol ligand at 0 °C for
24 h in toluene
¨
(Wahringer Str. 42, A-1090 Vienna). HPLC analysis was
b
Isolated yield after flash column chromatography
performed on a Thermo Finnigan (San Jose, CA, USA)
Surveyor chromatograph with a PDA plus detector
(190–360 nm). A Daicel Chiralcel OD-H column or Chir-
alpak AS-H column (250 9 4.60 mm) was used as the
c
Determined via HPLC on a Daicel Chiralcel OD-H or Chiralpak
AS-H column. The corresponding racemic alcohols were prepared by
the addition of an EtMgBr solution to the aldehyde and used for
comparison in HPLC analysis
123

Design, synthesis, and application of novel chiral ONN ligands
(d), 51.8 (t), 65.6 (d), 78.6 (d), 123.4 (d), 135.0 (s), 135.6 (d),
148.6 (d), 149.4 (d) ppm.
stationary phase with n-heptane/isopropanol as solvent and
a flow of 0.5–1.0 cm3/min; detection was performed at 254
and 219 nm. X-ray diffraction analysis was carried out
with a Bruker Smart APEX CCD diffractometer and Mo-
Ka radiation. Structure solution and refinement were per-
formed with the programs SHELXS97 and SHELXL9717.
(S)-3-Methyl-2-[[(pyridin-3-yl)methyl]amino]butan-1-ol
(9, C11H18N2O)
Preparation from 4.82 g of (S)-valinol (3, 46.7 mmol) [31]
according to general procedure A gave 9 as a yellow oil in
66 % yield. Rf = 0.28 (CH2Cl2:MeOH 30:1 ? Et3N);
General procedure A for the synthesis of ONN ligands
[a] = -6.5° cm3 g-1 dm-1 (EtOH, c = 1.45); 1H
20
589
NMR (200 MHz, CDCl3): d = 0.96/0.91 (2d, 6H,
Freshly distilled pyridine-3-carboxaldehyde (3.54 g,
33.1 mmol) was added to a mixture of the chiral starting
J = 6.9 Hz), 1.86 (m, 1H), 2.15 (br s, 2H, OH and NH),
2.74 (ddd, J1 = 6.5 Hz, J2 = 6.3 Hz, J3 = 4.0 Hz, 1H),
3.65/3.39 (2dd, J1 = 10.75 Hz, J2 = 4.16 Hz, J1 =
10.75 Hz, J2 = 6.98 Hz, 2H), 3.85/3.76 (2d, J = 13.3 Hz,
2H), 7.25 (dd, J1 = 8.0 Hz, J2 = 4.1 Hz, 1H), 7.68 (d,
J = 7.8 Hz, 1H), 8.49 (dd, J1 = 4.8 Hz, J2 = 1.6 Hz, 1H),
8.54 (d, J = 1.9 Hz, 1H) ppm; 13C NMR (50 MHz, CDCl3):
d = 18.2 (q), 19.2 (q), 28.5 (d), 48.7 (t), 60.5 (t), 63.8 (d),
123.3 (d), 135.8 (d), 136.1 (s), 148.1 (d), 149.2 (d) ppm.
˚
compound and 10 g of a 3 A activated molecular sieve in
100 cm3 of anhydrous methanol and refluxed for 14 h.
Sodium borohydride (1.25 g, 33.1 mmol) was added in
small portions and the mixture was stirred at room tem-
perature until TLC indicated complete conversion. The
reaction mixture was filtered over silica and hydrolyzed
with H2Odest. Methanol was removed under reduced pres-
sure and ethyl acetate was added to the residue. The
organic layer was extracted three times with small amounts
of water, dried over Na2SO4, filtrated and the remaining
solvent was removed under reduced pressure.
(S)-4-Methyl-2-[[(pyridin-3-yl)methyl]amino]pentan-1-ol
(10, C12H20N2O)
Preparation from 8.38 g of 4 (71.5 mmol) [32] according to
general procedure A gave 10 as a colorless liquid in 65 %
[S-(R*,S*)]-a-[1-[[(Pyridin-3-yl)methyl]amino]ethyl]
benzenemethanol (7, C15H18N2O)
yield.
20
589
Rf = 0.17
(CH2Cl2:MeOH
30:1 ? Et3N);
[a] = ? 14.8° cm3 g-1 dm-1 (EtOH, c = 1.02); m.p.:
Synthesis from 5.00 g (1S,2R)-norephedrine (1, 33.1 mmol)
according to general procedure A gave the crude product 7,
which was further purified via VFC (200 g silica,
CH2Cl2:MeOH 40:1 ? Et3N) to yield 7 as a light yellow
oil in 94 % yield. Rf = 0.29 (CH2Cl2:MeOH 30:1 ? Et3N);
40–42 °C; 1H NMR (200 MHz, CDCl3): d = 0.91/0.88
(2d, 6H, J = 2.9 Hz), 1.34 (m, 2H), 1.62 (m, 1H), 2.11 (br
s, 2H, OH and NH), 2.74 (ddd, J1 = 13.4 Hz, J2 = 6.3 Hz,
J3 = 3.9 Hz), 3.67/3.31 (2dd, J1 = 10.9 Hz, J2 = 3.8 Hz/
J1 = 10.8 Hz, J2 = 6.3 Hz), 3.85/3.77 (2d, J = 13.3 Hz),
7.26 (dd, J1 = 8.1 Hz, J2 = 4.4 Hz, 1H), 7.68 (d,
J = 7.8 Hz, 1H), 8.49 (dd, J1 = 4.9 Hz, J2 = 1.6 Hz,
1H, H-12), 8.54 (d, J = 2.0 Hz) ppm; 13C NMR (50 MHz,
CDCl3): d = 22.5 (q), 22.8 (q), 24.7 (d), 40.8 (t), 48.1 (t),
56.3 (d), 63.1 (t), 123.3 (d), 135.7 (s), 135.8 (d), 148.1 (d),
149.2 (d) ppm.
[a] = -13.3° cm3 g-1 dm-1 (EtOH, c = 1.00); 1H
20
589
NMR (200 MHz, CDCl3): d = 0.68 (d, J = 6.5 Hz, 3H),
2.70 (dq, J1 = 6.4 Hz, J2 = 4.3 Hz, 1H), 3.62/3.54 (2d,
J = 16. 4 Hz, 2H), 4.50 (d, J = 3.9 Hz, 1H), 7.06 (m, 6H),
7.38 (d, J = 7.8 Hz, 1H), 8.20 (m, 2H) ppm; 13C NMR
(50 MHz, CDCl3): d = 14.6 (q), 48.3 (t), 57.7 (d), 73.7 (d),
123.4 (d), 126.1 (d), 127.0 (d), 128.0 (d), 135.4 (s), 135.7 (d),
141.5 (s), 148.2 (d), 149.2 (d) ppm.
(S)-b-[[(Pyridin-3-yl)methyl]amino]benzenepropanol
(11, C15H18N2O)
[S-(2exo,3exo)]-1,7,7-Trimethyl-3-[[(pyridin-3-yl)
methyl]amino]bicyclo[2.2.1]heptan-2-ol
(8, C16H24N2O)
Preparation from 8.81 g of 5 (58.2 mmol) [31] according to
general procedure A and recrystallization from n-hexane/
ethyl acetate gave 11 as a white solid in 93 % yield.
Preparation from 6.49 g of 2 (38.3 mmol) [30] according to
general procedure A gave 8 as a colorless solid in 85 %
yield. Crystallization from n-hexane gave colorless crys-
20
589
Rf = 0.22 (CH2Cl2:MeOH 30:1 ? Et3N); [a]
=
-14.0° cm3 g-1 dm-1 (EtOH, c = 0.07); m.p.: 67–68 °C
(from n-hexane/ethyl acetate); 1H NMR (200 MHz,
CDCl3): d = 8.41 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H),
7.29–7.05 (m, 6H), 3.72 (s, 2H), 3.60 (dd, J1 = 10.7 Hz,
J2 = 3.7 Hz, 1H), 3.32 (dd, J1 = 8.0 Hz, J2 = 5.2 Hz,
1H), 2.88 (m, 1H), 2.75 (s, 1H), 2.71 (d, 1H), 1.92 (bs, 2H)
ppm; 13C NMR (50 MHz, CDCl3): d = 37.9 (t), 48.6 (t),
59.6 (d), 62.7 (d), 123.6 (d), 126.7 (d), 128.6 (2d), 129.1
(2d), 135.2 (s), 135.7 (d), 138.2 (s), 148.6 (d), 149.6
(d) ppm.
20
589
tals. Rf = 0.22 (CH2Cl2:MeOH 30:1 ? Et3N); [a]
=
? 13.9° cm3 g-1 dm-1 (EtOH, c = 1.00); m.p.: 44–47 °C
(from n-hexane); H NMR (200 MHz, CDCl3): d = 0.94/
1
0.77 (2s, 6H), 0.99 (m, 2H), 1.04 (s, 3H), 1.79–1.16 (m, 3H),
2.79 (d, J = 7.2 Hz, 1H), 3.43 (d, J = 7.2 Hz, 1H), 3.86/
3.78 (2dd, J1 = 13.5 Hz, 2H), 4.30 (br s, 1H, OH), 7.27 (dd,
J1 = 7.5 Hz, J2 = 5.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H),
8.54 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): d = 11.2
(q), 21.2 (q), 21.8 (q), 27.0 (t), 32.7 (q), 46.5 (s), 48.7 (s), 51.4
123

K. Bica et al.
(S)-1-[(Pyridin-3-yl)methyl]pyrrolidine-2-methanol
(12, C18H16N2O)
J1 = 7.8 Hz, J2 = 4.9 Hz), 7.32 (m, 5H), 7.43 (d,
J = 7.8 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.43 (dd,
J1 = 4.8 Hz, J2 = 1.5 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 14.6 (q), 38.1 (q), 55.9 (t), 63.6 (d), 74.4 (d),
123.2 (d), 126.2 (d), 126.9 (d), 127.9 (d), 135.0 (s), 136.2 (d),
143.3(s), 148.0 (d), 149.6 (d) ppm.
(S)-Prolinol (6, 6.56 g, 64.9 mmol) [33] and 6.95 g of
freshly distilled pyridine-3-carbaldehyde (64.9 mmol) were
dissolved in 100 cm3 of anhydrous acetonitrile and stirred at
room temperature for 12 h. The solvent was removed under
reduced pressure and the crude material was dissolved in
80 cm3 of anhydrous methanol. NaBH4 was added in small
portions and the mixture was stirred for 2 h at room
temperature until TLC indicated complete conversion. The
reaction mixture was carefully hydrolyzed with 50 cm3 H2O
and the methanol was removed under reduced pressure. The
aqueous solution was extracted with diethyl ether. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The
crude product was purified over silica (CH2Cl2:MeOH
[S-(2exo,3exo)]-1,7,7-Trimethyl-3-[methyl[(pyridin-3-yl)
methyl]amino]bicyclo[2.2.1]heptan-2-ol
(14, C17H26N2O)
Preparation from 2.75 g of 8 (10.6 mmol) according to
general procedure B gave 14 as a light yellow oil in 82 %
20
589
yield. Rf = 0.38 (CH2Cl2:MeOH 30:1 ? Et3N); [a]
=
-3.8° cm3 g-1 dm-1 (EtOH, c = 1.14); 1H NMR
(200 MHz, CDCl3): d = 0.92/0.72 (2s, 6H), 0.96 (m, 2H),
1.05 (s, 3H), 1.69/1.39 (2m, 2H), 2.07 (m, 4H), 2.49 (d,
J = 7.04 Hz, 1H), 3.43 (m, 3H), 4.13 (br s, 1H, OH), 7.22
(dd, J1 = 7.7 Hz, J2 = 4.8 Hz, 1H), 7.57 (d, J = 7.8 Hz,
1H), 8.44 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
d = 11.6 (q), 21.2 (q), 22.1 (q), 28.0 (t), 32.3 (t), 40.5 (br q),
46.7 (d), 46.9 (s), 49.4 (d), 59.2 (br t), 73.5 (d), 79.2 (d), 123.5
(d), 133.9 (s), 136.5 (d), 148.9 (d), 150.4 (d) ppm.
30:1 ? Et3N) to yield 12 as a light brown oil in 93 % yield.
20
589
Rf = 0.43 (CH2Cl2:MeOH 20:1 ? Et3N); [a]
=
1
? 73.9° cm3 g-1 dm-1 (EtOH, c = 1.02); H NMR (200
MHz, CDCl3): d = 2.06–1.59 (m, 4H), 2.25 (m, 1H), 2. 73
(ddd, J1 = 11.9 Hz, J2 = 5.8 Hz, J3 = 2.9 Hz, 1H), 2.94
(m, 2H), 3.65/3.46 (2dd, J1 = 11.0 Hz, J2 = 3.7 Hz/
J1 = 11.0 Hz, J2 = 2.5 Hz, 2H), 3.99/3.35 (2d,
J = 13.3 Hz, 2H), 7.23 (dd, J1 = 7.8 Hz, J2 = 4.7 Hz,
1H), 7.63 (dt, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 8.47 (dd,
J1 = 5.1 Hz, J2 = 2.0 Hz, 1H), 8.50 (d, J = 2.7 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3): d = 23.1 (t), 27.5 (t),
55.8/54.2 (2), 62.3 (t), 64.4 (d), 123.2 (d), 134.6 (s), 136.3 (d),
148.2 (d), 149.8 (d) ppm.
(S)-3-Methyl-2-[methyl[(pyridin-3-yl)methyl]amino]
butan-1-ol (15, C12H20N2O)
Preparation from 0.707 g of 9 (3.64 mmol) according
general procedure B gave 15 as a light yellow oil in 97 %
20
589
yield. Rf = 0.33 (CH2Cl2:MeOH 30:1 ? Et3N); [a]
=
-19.6° cm3 g-1 dm-1 (EtOH, c = 1.00); 1H NMR
(200 MHz, CDCl3): d = 1.09/0.89 (2d, 6H, J = 6.5 Hz),
1.68 (br s, 1H, OH), 1.93 (m, 1H), 2.15 (br s, 2H, OH and
NH), 2.27 (s, 3H), 2.52 (ddd, J1 = 10.0 Hz, J2 = 8.6,
J3 = 4.7 Hz, 1H), 3.34 (m, 1H), 3.66 (dd, J1 = 10.7 Hz,
J2 = 5.0 Hz, 1H), 3.88/3.74 (2d, J = 13.5 Hz, 2H), 7.27
(dd, J1 = 8.0 Hz, J2 = 4.2 Hz, 1H), 7.63 (ddd,
J1 = 7.8 Hz, J2 = 1.9 Hz, J3 = 1.9 Hz, 1H), 8.51 (s, 2H)
ppm; 13C NMR (50 MHz, CDCl3): d = 19.8 (q), 22.1 (q),
27.8 (d), 35.9 (q), 58.9 (t), 59.4 (t), 70.7 (d), 123.4 (d), 135.2
(s), 136.2 (d), 148.3 (d), 149.8 (d) ppm.
General procedure B
Compounds 7–11, prepared according to procedure A,
were dissolved in 30 cm3 of concentrated formic acid and
stirred for 30 min. Formaldehyde (25 cm3, 37 % solution
in H2O) was added and the mixture was refluxed overnight.
Remaining formaldehyde was removed under reduced
pressure, 4 M NaOH solution in H2O was added until pH
[7, and the reaction mixture was extracted with CH2Cl2.
The organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to yield
the crude products.
(S)-4-Methyl-2-[methyl[(pyridin-3-yl)methyl]amino]
pentan-1-ol (16, C13H22N2O)
Preparation from 4.99 g of 10 (24.0 mmol) according to
general procedure B gave 16 as a light yellow oil in 89 %
20
[S-(R*,S*)]-a-[1-[Methyl[(pyridin-3-yl)methyl]amino]-
ethyl]benzenemethanol (13, C16H20N2O)
yield. Rf = 0.33 (CH2Cl2:MeOH 30:1 ? Et3N); [a]
=
589
? 3.4° cm3 g-1 dm-1 (EtOH, c = 1.01); 1H NMR
(200 MHz, CDCl3): d = 0.93/0.60 (2d, 6H, J = 6.7 Hz),
1.08 (dq, J1 = 13.4 Hz, J2 = 4.6 Hz, 1H), 1.45 (m, 2H), 1.45
(m, 2H), 2.75 (s, 3H), 2.86 (m, 1H), 3.41 (m, 3H), 3.70/3.50
(2d, J = 13.3 Hz/J = 13.5 Hz), 7.26 (dd, J1 = 7.8 Hz,
J2 = 4.3 Hz, 1H), 7.64 (d, J = 7.83 Hz, 1H), 8.50 (m, 2H)
ppm; 13C NMR (50 MHz, CDCl3): d = 22.0 (q), 23.5 (q),
25.1 (d), 33.8 (t), 35.5 (q), 55.1 (t), 61.1 (t), 61.7 (d), 123.3 (d),
134.6 (s), 136.3 (d), 148.5 (d), 150.0 (d) ppm.
Synthesis starting from 4.30 g compound 7 (17.74 mmol)
yielded crude 13. Crystallization from n-hexane/ethyl acetate
gave 13 as colorless crystals in 89 % yield. Rf = 0.24
(CH2Cl2:MeOH 30:1 ? Et3N); [a] = -10.5° cm3 g-1
20
589
dm-1 (EtOH, c = 1.08); m.p.: 106–108 °C (from n-hexane/
1
ethyl acetate); H NMR (200 MHz, CDCl3): d = 1.08 (d,
J = 6.9 Hz, 3H), 2.19 (s, 3H), 2.92 (m, 1H), 3.59 (s, 2H), 3.67
(br s, 1H, OH), 4.83 (d, 1H, J = 5.5 Hz), 7.17 (dd,
123

Design, synthesis, and application of novel chiral ONN ligands
3. Mukayama T, Suzuki K, Soai K, Sato T (1979) Chem Lett 447
4. Sato T, Soai K, Suzuki K, Mukayama T (1978) Chem Lett 601
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Catal A Chem 286:106
8. Soai K, Niwa S (1992) Chem Rev 92:833
(S)-b-[Methyl[(pyridin-3-yl)methyl]amino]
benzenepropanol (17, C16H20N2O)
Preparation from 5.32 g of 11 (20.8 mmol) according to
general procedure B gave 17 as a light yellow oil in 56 %
yield (3.14 g). Rf = 0.16 (CH2Cl2:MeOH 20:1 ? Et3N);
[a] = -16.6° cm3 g-1 dm-1 (CHCl3, c = 1.05); 1H
20
589
NMR (200 MHz, CDCl3): d = 8.42 (m, 2H), 7.55 (d,
¨
9. Bulut A, Aslan A, Izgu¨ EC, Dogan O (2007) Tetrahedron
Asymmetry 18:1013
10. Kawamura K, Fukuzawa H, Hayashi M (2008) Org Lett 10:3509
11. Yang XF, Hirose T, Zhang GY (2008) Tetrahedron Asymmetry
19:1670
12. Le Goanvic D, Holler M, Pale P (2002) Tetrahedron Asymmetry
13:119
13. Murtagh K, Sweetman BA, Guiry PJ (2006) Pure Appl Chem
78:311
J = 9.6 Hz, 1H), 7.28–7.20 (m, 6H), 3.74–3.45 (dd,
J1 = 33.5 Hz, J2 = 13.4 Hz, 2H), 3.38 (m, 2H),
3.08–2.75 (m, 3H), 2.36 (dd, J1 = 13.0 Hz, J2 = 8.9 Hz,
1H), 2.21 (s, 3H) ppm; 13C NMR (50 MHz, CDCl3):
d = 31.6 (t), 35.8 (q), 55.7 (t), 60.6 (t), 65.8 (d), 123.6 (d),
126.3 (d), 128.6 (2d), 129.1 (2d), 134.4 (s), 136.5 (d), 139.0
(s), 148.7 (d), 150.1 (d) ppm.
14. Mao J, Wan B, Zhang Z, Wang R, Wu F, Lu S (2005) J Mol Catal
A Chem 225:33
15. Bisai A, Singh KP, Singh VK (2007) Tetrahedron 63:598
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18. de las Casas Engel T, Maroto BL, Martinez AG, de la Moya
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27. Noyori R, Suga S, Kawai K, Okada S, Kitamura M, Oguni N,
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28. Harada T, Kanda K (2006) Org Lett 8:3817
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30. Ramalingam B, Chinpiao C, Gene-Hsian L (2012) Org Biomol
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Asymmetry 22:797
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133:7065
Asymmetric diethyl zinc alkylation of aromatic
aldehydes
The chiral ligand (0.2 mmol) was dissolved in 4 cm3 of
anhydrous toluene under a dry argon atmosphere and
cooled to 0 °C. A solution of diethyl zinc (1.0 M in
n-hexane, 4.4 mmol) was added slowly at 0 °C. After the
reaction had been stirred for 30 min, freshly distilled
aldehyde (2 mmol) was added dropwise via a microsyringe
at 0 °C, and the reaction was stirred for 8 h at room tem-
perature. The mixture was carefully hydrolyzed with 1 M
HCl and the aqueous phase was extracted with diethyl
ether. The combined organic layers were washed with a
small amount of brine, dried over anhydrous Na2SO4, fil-
tered, and concentrated. The residue was purified by flash
column chromatography (30 g silica, light petrol:diethyl
ether) to yield the secondary alcohol 19. HPLC: Chiralcel
OD-H; n-hexane:isopropanol 98:2; 0.7 cm3/min; 254 nm.
Analytical data were in agreement with those reported in
the literature [17–19].
¨
Acknowledgments Financial support by the Hochschuljubilaumss-
tiftung der Stadt Wien is gratefully acknowledged. This research was
partly funded by the fFORTE WIT-Women in Technology Program
of the Vienna University of Technology. This program is co-financed
by the Vienna University of Technology, the Austrian Federal Min-
istry for Science and Research, and the fFORTE Initiative of the
Austrian Government.
References
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841
123