Modular iminopyridine ligands. Application to the enantioselective copper(II)-catalyzed Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2006.07.025

Chiral iminopyridines prepared in a modular fashion from monoterpenic (camphor-derived) ketones and pyridinylalkylamines catalyze the enantioselective Henry (nitro aldol) reaction between nitromethane and o-anisol in the presence of copper(II) acetate, wi

Full text of DOI:10.1016/j.tetasy.2006.07.025

Tetrahedron: Asymmetry 17 (2006) 2046–2049
Modular iminopyridine ligands. Application to the
enantioselective copper(II)-catalyzed Henry reaction
*
´
´
´
Gonzalo Blay, Estela Climent, Isabel Fernandez, Victor Hernandez-Olmos and Jose R. Pedro
` ` `
´
Departament de Quı´mica Organica, Facultat de Quımica, Universitat de Valencia, Dr. Moliner 50, E-46100-Burjassot, Valencia, Spain
Received 23 May 2006; accepted 19 July 2006
Abstract—Chiral iminopyridines prepared in a modular fashion from monoterpenic (camphor-derived) ketones and pyridinylalkyl-
amines catalyze the enantioselective Henry (nitro aldol) reaction between nitromethane and o-anisol in the presence of copper(II) ace-
tate, with high yields and good ee (up to 86%) under straightforward experimental conditions without the need for air or moisture
exclusion.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
Ligands bearing two N (sp2) coordinating atoms have
found wide application in enantioselective metal-catalyzed
reactions.1 Great attention has been dedicated to C2-
symmetric N,N-ligands such as bis-imines,2 bis-pyridines,3
and, especially, bis-oxazolines.4 Furthermore, C1-symmet-
ric5 ligands with two sterically and electronically differ-
N
N
N
N
N
N
Ar
Ar
R
R
R
R
bis-imine
bis-pyridine
bis-oxazoline
O
R'
N
N
R
N
N
R'
R''
entiated
N
(sp2) have also been developed. Thus,
R
oxazolinylpyridines, introduced by Brunner,6 have received
some attention,7 as well as iminopyridines derived from 2-
pyridine carboxaldehyde and chiral amines.8 However, to
the best of our knowledge, iminopyridines derived from
chiral ketones have never been used as ligands in asymmet-
ric catalysis.9 According to this last strategy, we have devel-
oped new iminopyridine type ligands based on the design
of Figure 1, which allow high modularity by changing
the ketone, the spacer and the substitution on the pyridine
ring.
oxazolinylpyridine
Iminopyridine
spacer
spacer
N
Mn+
N
N
Chiral
ketone
Chiral
N
ketone
Mn+
R
R
Figure 1. C2 and C1 N,N-ligands and design of modular iminopyridine
chiral ligands.
The Henry (or nitroaldol) reaction is one of the most con-
venient reactions for direct carbon–carbon bond formation
to give b-hydroxynitroalkanes.10 Due to the versatile chem-
istry of the nitro group,11 the reaction provides access to
valuable structural motifs such as 1,2-amino alcohols and
a-hydroxy acids by reduction to amines or by the Nef reac-
tion, respectively. Therefore, considerable effort has been
directed over recent years towards the development of the
catalytic asymmetric version of this reaction. Examples in-
clude the use of metal-based bifunctional chiral catalysts,
which rely on concurrent activation of the aldehyde and
the nitroalkanes.12 Independent activation of the aldehyde
and nitroalkane has also been achieved by the combined
use of metal complexes and a Bronsted base13 or by
the use of silyl nitronates.14 Some of these systems are
*
Corresponding author. Tel.: +34 963544329; fax: +34 963544328;
e-mail: jose.r.pedro@uv.es
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.025

G. Blay et al. / Tetrahedron: Asymmetry 17 (2006) 2046–2049
2047
moisture or air sensitive and require the use of an inert
atmosphere.
OH
OMe
OMe
NO2
CHO
Ligand, M(OAc)n
Base, solvent
+
CH3NO2
Bis-oxazoline-based complexes have been successfully
used as catalysts for the enantioselective Henry reaction,
either with concurrent or independent activation of both
reagents.12e,13a,b,14 In the view of this, we decided to
study the activity of the designed iminopyridines as cata-
lysts in the Henry reaction. Herein, we report our prelimin-
ary results on this reaction, which is the first example of the
application of this kind of ligands in enantioselective
metal-catalyzed reactions.
Scheme 2. Henry (nitro aldol) reaction between nitromethane and
o-anisol.
According to the reaction conditions described by Evans
for the bis-oxazoline-copper catalyzed Henry reaction12e
the reaction was initially carried out at room temperature
in ethanol using 10 mol % acetate as the source for the me-
tal ion. The reactions were performed in test tubes stopped
with a septum with no special attention given for air or
moisture exclusion. Screening of some late transition metal
acetates showed copper acetate to be the best promoter for
this reaction (Table 1, entry 5). When copper(II) triflate
was used, the reaction gave the corresponding nitroalkene,
resulting from elimination. Ethanol was found to be supe-
rior to other solvents tested (entries 6–9). Ligands 4–9
were also tested under similar reaction conditions. It was
observed that the elongation (entry 11) and introduction
of substituents (entry 10) on the spacer which alter the bite
angle of the ligand had a negative effect. Similarly, the
introduction of steric hindrance in the proximities of the
pyridine (entry 12) or the imine (entry 13) nitrogen
brought about a decrease in enantioselectivity. Ligand 9
derived from (1R)-(ꢀ)-fenchone gave the expected product
with the same configuration and in similar ee as ligand 3
(entry 14). Further improvements of the reaction were car-
ried out with the combination 3-Cu(II)OAc. Since copper
acetate can catalyze the non-enantioselective background
reaction, the reaction temperature was lowered in order
to increase the enantioselectivity. Thus, at 0 °C, the enan-
tiomeric excess increased up to 67% (entry 15). Unfortu-
nately, lowering the reaction temperature to ꢀ20 °C
resulted in impractical reaction times. The addition of a
Bronsted base (entries 16–21) accelerated the reaction
and allowed us to lower the reaction temperature to
ꢀ65 °C, which brought about a noticeable increase in
the ee of the product. Diisopropylethylamine (DIPEA)
gave the best results (up to 85% ee) when used in either
stoichiometric (entry 18) or catalytic amounts (entry 19).
Finally, variations in the catalyst loading (entries 20 and
21) did not give a significant variation in the result of
the reaction.
2. Results and discussion
A set of ligands 3–8 based on the camphane and fenchane
frameworks were synthesized.15 Ligands 3, 5 and 6 were
prepared in one step by condensation of commercially
available (1R)-(+)-camphor with the corresponding pyr-
idinylalkylamines according to Scheme 1.16 Ligand 4 was
obtained from ligand 3 via a double alkylation at the benz-
ylic position with BuLi and MeI.9d Ligand 7 was synthe-
sized by the condensation between picolylamine and a
ketone prepared by a Grignard synthesis from (1S)-(+)-
ketopinic acid methyl ester.17 Finally, direct condensation
of picolylamine and (1R)-fenchone, both of which are com-
mercially available, afforded ligand 8. These ligands differ
on the substitution and length of the spacer, and on the ste-
ric hindrance in the proximities of the pyridine and imine
nitrogens.
NH2
.
BF3 Et2O
N
N
N
+
Tol (-H2O)
O
3
2
1
N
N
N
N
4
5
N
N
N
N
OH
Ph
Ph
6
7
3. Conclusion
In conclusion we have developed a type kind of N,N-li-
gand, which can be used in enantioselective metal-catalyzed
reactions. These ligands can form complexes with different
late transition metals. The copper(II)-complex generated
in situ catalyzes the Henry reaction between nitromethane
and o-anisol with excellent yield and high enantioselectivity
under straightforward experimental conditions.18 The
study of the scope of this reaction, the preparation of
new ligands from chiral ketones and pyridinylalkylamines
and their application in other catalytic enantioselective
reactions is currently in progress.
N
N
8
Scheme 1. Synthesis of iminopyridine ligands derived from monoterpenic
ketones and pyridinylalkylamines.
The reaction between nitromethane and o-anisole was used
to test the ability of these ligands to induce enantioselec-
tivity in the metal-catalyzed Henry reaction (Scheme 2).

2048
G. Blay et al. / Tetrahedron: Asymmetry 17 (2006) 2046–2049
Table 1. Henry reaction between nitromethane and o-anisol according to Scheme 2
Entry
Ligand (11 mol %)
Metal salt (10 mol %)
Solvent
Base (1 equiv)
T (°C)
t (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
3
Co(OAc)3Æ2H2O
Ni(OAc)2Æ4H2O
Zn(OAc)2Æ2H2O
Pd(OAc)2ÆH2O
Cu(OAc)2ÆH2Oe
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O
Cu(OAc)2ÆH2O (20 mol %)
Cu(OAc)2ÆH2O (5 mol %)
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
MeNO2
CH2Cl2
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Cy2NH
Et3N
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
24
93
70
24
24
70
70
24
64
26
64
70
24
88
45
88
48
70
70
70
94
94
77
40c
93
95
90
62c
54c
45c
62
47c
95
77
98
84
56
90
92
96
94
rac
rac
ꢀ10d
37
61
53
48
49
52
21
19
16
7
61
67
80
83
85
83
86
84
3
3
3
3
3
3
3
3
4
5
6
7
8
3
0
3
ꢀ65
ꢀ65
ꢀ65
ꢀ55
ꢀ65
ꢀ65
3
3
DIPEA
DIPEA (0.1 equiv)
DIPEA
DIPEA
3
3 (22 mol %)
3 (6 mol %)
a Yields refer to isolated product after column chromatography.
b Determined by HPLC analysis using a Chiralcel OD-H column. The (S)-enantiomer was obtained unless otherwise stated.
c Uncomplete reaction after the indicated time.
d The (R) enantiomer was obtained.
e Under similar reaction conditions, Cu(OTf)2 gave the corresponding nitroalkene.
Soc. 2001, 123, 8444–8445; (d) Nugent, W. A. Org. Lett.
2002, 4, 2133–2136; (e) Cohn, A. J. A.; Marson, C. M.
Tetrahedron: Asymmetry 2001, 12, 1547–1550; (f) Wipf, P.;
Wang, X. Org. Lett. 2002, 4, 1197–1200; (g) Preigo, J.;
Mancheno, O. G.; Cabrera, S.; Carretero, J. C. J. Org. Chem.
2002, 67, 1346–1353; For a discussion on C1 symmetric
ligands see also: (h) Humphries, A. C.; Pfaltz, A. In
Stimulating Concepts in Chemistry; Vo¨tgle, F., Stoddart, J.
F., Shibashaki, M., Eds.; Wiley-VCH: Weinheim, 2000; pp
89–103.
Acknowledgments
Financial support from Generalitat Valenciana (Grant
GV 05/10) and from the Universitat de Valencia (Grant
UV-AE-20060244) is gratefully acknowledged. V.H-O.
`
`
thanks the Universitat de Valencia by a pre-doctoral grant
(V Segles program).
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25
25
½aꢁD = ꢀ24.2 (c 0.91, CHCl3), ½aꢁD = ꢀ30.4 (c 0.81, MeOH);
MS(EI) 242 (M+, 58), 241 (100), 92 (78); HRMS 242.1772,
1
C16H22N2 required 242.1783; H NMR (300 MHz, CDCl3) d
8.50 (dd, J = 5.0, 1.8 Hz, 1H), 7.66 (td, J = 7.5, 1.8 Hz, 1H),
7.50 (d, J = 7.5 Hz, 1H), 7.14 (dd, J = 7.5, 5.0 Hz, 1H), 4.65
(d, J = 16.2 Hz, 1H), 4.61 (d, J = 16.2 Hz, 1H), 2.54 (dt,
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4.2 Hz, 1H), 1.44 (ddd, J = 12.0, 9.0, 4.2 Hz, 1H), 1.24 (ddd,
J = 12.0, 9.0, 4.2 Hz), 1.11 (s, 3H), 0.95 (s, 3H), 0.78 (s, 3H);
13C NMR (75 MHz, CDCl3) d 184.5 (s), 160.6 (s), 148.8 (d),
136.4 (d), 121.4 (d), 121.4 (d), 57.5 (t), 53.9 (s), 47.2 (s), 43.8
(d), 35.9 (t), 32.1 (t), 27.3 (t), 19.5 (q), 18.9 (q), 11.3 (q).
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18. Typical experimental procedure for the enantioselective
Henry reaction catalyzed by 3: Cu(OAc)2ÆH2O (9.9 mg,
0.05 mmol) was added to a solution of compound 3 (15 mg,
0.055 mmol) in absolute EtOH (1.5 mL) and the mixture
stirred for 1 h. To the resulting blue solution was added
nitromethane (0.27 mL, 5 mmol) and the recipient was
introduced in a bath at ꢀ65 °C. o-Anisol (68 mg, 0.5 mmol)
dissolved in absolute ethanol (1.5 mL) was added followed by
DIPEA (82 lL, 0.5 mmol) and the reaction mixture was
stirred until completion (TLC). The solvent was removed
under reduced pressure and the residue chromatographed on
silica gel (hexane:diethyl ether, 85:15) to give 89 mg of (S)-1-
(2-methoxyphenyl)-2-nitroethanol: Enantiomeric excess was
determined by HPLC (Chiralcel OD-H), hexane:i-PrOH
90:10, 1 mL/min, major enantiomer (S)tr = 13.6, minor
´
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´
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´
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25
287; (i) Bulanksananusorn, T.; Knochel, P. J. Org. Chem.
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2004, 69, 4595–4601; (j) Jeon, S.; Li, H.; Garcıa, C.;
CH2Cl2, ee 85%); 1H NMR (CDCl3) d 7.44 (dd, J = 7.5,
1.5 Hz, 1H), 7.33 (td, J = 7.5, 1.5 Hz, 1H), 7.04–6.99 (m, 1H),
6.91 (d, J = 8.4 Hz, 1H), 5.63 (dd, J = 9.0, 3.3 Hz, 1H), 4.65
(dd, J = 13.2, 3.3 Hz, 1H), 4.57 (dd, J = 13.2, 9.0 Hz, 1H),
3.88 (s, 3H), 2.87 (s, 1H); 13C NMR (CDCl3) d 155.9, 129.7,
127.1, 125.9, 121.0, 110.5, 79.8, 67.7, 55.3.
´
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16. Synthesis of ligand 3: A solution of (+)-camphor (6.0 g,
41.8 mmol), picolylamine (4.27 mL, 41.8 mmol) and