Enantioselective nitroaldol (Henry) reaction using copper(II) complexes of (-)-sparteine

Article abstract of DOI:10.1039/b610203d

The dichloro[(-)-sparteine-N,N′]copper(ii) complex provides Henry adducts with high enantioselectivities (73-97% ee) in Henry reaction between nitromethane and various aldehydes. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b610203d

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Enantioselective nitroaldol (Henry) reaction using copper(II) complexes
of (2)-sparteine{
a
H. Maheswaran,* K. Leon Prasanth, G. Gopi Krishna, K. Ravikumar, B. Sridhar and
a
a
b
b
a
M. Lakshmi Kantam
Received (in Cambridge, UK) 17th July 2006, Accepted 29th August 2006
First published as an Advance Article on the web 14th September 2006
DOI: 10.1039/b610203d
The dichloro[(2)-sparteine-N,N9]copper(II) complex provides
Henry adducts with high enantioselectivities (73–97% ee) in
Henry reaction between nitromethane and various aldehydes.
structure of the complexes semi-rigid, stereochemically well
14
defined, and conformationally less flexible.
Two different copper(II) complexes of (2)-sparteine were
9,10
synthesized by following a procedure described previously; they
are namely, diacetatato[(2)-sparteine-N,N9]copper(II) (1), and
dichloro[(2)-sparteine-N,N9]copper(II) (2). These complexes in
crystalline form were then screened as catalysts for the AH
reaction between 4-nitrobenzaldehyde and nitromethane in various
solvents at ambient temperature. Table 1 presents some repre-
sentative results from the screening.
The Henry reaction constitutes a fundamental carbon–carbon
bond forming reaction in organic chemistry, which has been used
1
for the construction of numerous useful compounds. The nitro
2
group of these products can undergo the Nef reaction, reduction
3
to an amino group, or nucleophilic displacement. The catalytic
asymmetric Henry reaction (AH reaction) has been successfully
implemented only in a very few cases. For example, the AH
reactions with impressive enantioselectivity are realized using
Catalyst 1 directly catalyzes the Henry reaction with nitro-
methane, and affords excellent yields of the Henry adducts in a
variety of solvents, without requiring base promoters such as
triethylamine (entries 1–4). Apparently, Lewis acidic copper(II)
4
heterobimetallic catalysts (rare earth–lithium–BINOL complexes),
5
dinuclear zinc chiral semi-azacrown complexes, chiral bisoxazo-
6
line copper(II) complexes, and zinc–chiral (+)-N-methyl ephedrine
7
complexes. In this communication, we report a new catalytic
protocol for the AH reaction using divalent copper complexes
derived from quinolizidine alkaloid (2)-sparteine. The impact of
sparteine as a chiral ligand in asymmetric synthesis, particularly in
organolithium chemistry, has been incredible and, more recently,
the use has been extended to other metal ions such as Mg, Pd, Zn,
Table 1 Screening of reaction parameters for the reaction of
nitromethane with 4-nitrobenzaldehyde using copper(II)-(2)-sparteine
complexes
a
8
and Cu.
The most interesting aspect of copper(II) complexes with (2)-
sparteine is present in their configurational and conformational
features. For example, the structure of divalent [(2)-sparteine-
9
10
Et
3
N
Yield ee
c d
N,N9]copper(II) complex in solid-state and in solution has
b
Entry Catalyst Solvent (mol%) Temp/uC Time/h (%) (%)
indicated that the copper atom in this complex is four-coordinate,
1
1
1
2
3
4
5
6
7
8
9
0
1
2
3
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
DCM
DMF
THF
MeOH
DCM
DCM
DMF
0
0
0
0
0
3
0
35
35
35
35
35
35
35
35
35
35
35
35
35
35
0
20
20
20
20
48
24
24
24
10
48
20
12
07
04
18
.95 ,4 (R)
.95 ,4 (R)
.95 ,4 (R)
.95 ,4 (R)
and has distorted tetrahedral geometry. The formation of the
complex leads to a conversion of the nitrogen atom configuration
in the sparteine ligand; as a consequence, all the four alkaloid rings
adopt chair conformations, and configuration at the A/B and C/D
,5
82
33
70
95
,5
50
90
95
95
90
nd
9,12
,4 (R)
37 (R)
33 (R)
16 (R)
nd
57 (R)
73 (R)
60 (R)
49 (R)
86 (R)
ring junctions are trans and cis, respectively. This conformation
differs from that of free (2)-sparteine ligand, in which the C-ring
takes the boat form, and the configuration at the C/D ring-
DMF 1.5
DMF
MeOH
3
0
1
3
1
1
1
1
junction is trans. This stereochemical outcome in the copper(II)
MeOH 1.5
MeOH
MeOH 4.5
complex is precisely due to sterically demanding fused rings of
9–13
sparteine.
3
Thus, the formation of (2)-sparteine complexes in
which tertiary diamine acts as a bidentate ligand demands a very
precise stereochemical conditions. This invariably makes the
14
1
MeOH
MeOH
6
3
5
a
All reactions were performed on a 0.5 mmol scale with 20 mol% of
catalyst and 2.0 equiv. of nitromethane in 1 mL solvent at the
indicated temperature. Amount of Et N is expressed in mol%
relative to aldehyde substrate. Values are isolated yields after
chromatographic purification.
determined by HPLC using Chiralcel OD-H column using
isopropanol and hexane; the absolute configuration (R-isomer or
S-isomer) of the Henry adduct was assigned by comparison with
a
IPC Division, Indian Institute of Chemical Technology, Hyderabad,
b
3
India. E-mail: maheswaran_dr@yahoo.com; Fax: 91 4027160921;
Tel: 91 4027193510
X-ray Crystallography Centre, Indian Institute of Chemical
c
d
Enantiomeric excess (ee) was
b
Technology, Hyderabad, India
{ Electronic supplementary information (ESI) available: Synthesis and
characterization of complexes 1 and 2, reaction procedure, NMR, and
4a,6a,18
optical rotation data of known compound.
HPLC data for Henry adducts. See DOI: 10.1039/b610203d
4
066 | Chem. Commun., 2006, 4066–4068
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complex 1 bearing moderately charged acetate anions facilitate
Table 2 Asymmetric Henry reaction of nitromethane with various
aldehydes catalyzed by dichloro[(2)-sparteine-N,N9]copper(II) (2)
a
deprotonation of nitromethane as a prelude to the aldol addition
6a
process. Nevertheless, this reaction was nonstereoselective
because very poor ee values (,4%) for nitroaldol products were
obtained (entries 1–4). Similar results were obtained when other
aromatic aldehydes such as benzaldehyde, 4-chlorobenzaldehyde,
and 4-methoxybenzaldehyde were evaluated under similar reaction
conditions.
In contrast, when catalyst 2 was screened under similar
conditions, Henry reaction proceeded in a sluggish manner and
gave very poor yields in the solvents studied; ,5% conversion in
dichloromethane and methanol, and 33% in DMF (entries 5, 7,
and 10). Base promoters such as triethylamine significantly
increase both the speed and the yield of this reaction (entries 5–
b
c
Entry
Substrate
Product
Time/h
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
12
18
14
11
07
16
24
24
24
24
24
24
.95
90
80
.95
.95
80
60
82
85
78
80
84
79 (R)
86 (R)
89 (R)
80 (R)
97 (R)
81 (R)
96 (R)
73 (R)
85 (R)
78 (R)
90 (R)
81 (R)
1
5); thus, catalyst 2 could only be activated toward the Henry
15
reaction under double catalytic activation (DCA) conditions.
Surprisingly, excellent ee values up to 73–86% were obtained for
the Henry adducts in methanol (entries 12,15). Moreover, the
degree of chiral induction observed with 2 depends not only on the
nature of the solvent used but also on the quantity of triethylamine
base used (see Table 1). For example, both dichloromethane and
DMF were very poor solvents for the catalytic AH reaction as low
ee values were obtained (entries 6, 8–9). In fact, increase in the
amount of triethylamine base lowers the enantioselectivity of the
nitroaldol product from 33% to 16% in DMF (entries 6–8).
Methanol is the best solvent for the catalytic AH reaction when
catalyst 2 was used in combination with triethylamine. Increasing
the amount of triethylamine also results in a drop in ee values
1
1
0
1
1j
1k
1l
3j
3k
3l
12
a
All reactions were performed on a 0.5 mmol scale with 20 mol% of
catalyst, triethylamine (3 mol% relative to aldehyde), and 2.0 equiv.
of nitromethane in 1 mL methanol at 0 uC. Values are isolated
yields after chromatographic purification. Enantiomeric excess (ee)
was determined by HPLC using Chiralcel OD-H, OJ-H, or AD
columns using isopropanol and hexanes; the absolute configuration
(R-isomer or S-isomer) of the Henry products were assigned by
comparison with optical rotation data of known compounds.
b
c
(entries 10–14); however the optimum amount of triethylamine
4a,6a,18
that is needed to achieve good conversion (90%) and enantio-
selectivity (73%) at 35 uC is 3 mol% relative to the substrate
(entry 12). As the temperature decreases, ee increases remarkably
with a decrease in the rate of reaction. At 0 uC, the AH reaction
between 4-nitrobenzaldehyde and nitromethane gave 86% ee for
the Henry adduct (entry 15).
With optimised conditions in hand, the scope of the reaction
was explored (Table 2). In general, high enantiomeric excesses (73–
97% ee) are observed at 0 uC for aromatic aldehydes bearing either
electron-withdrawing or electron-donating groups (entries 1–8). In
particular, the aromatic aldehydes bearing substituents in the ortho
position, gave high enantioselectivities (entries 3, 5, 7). The reason
for this appears to be more steric in nature because ortho
substituents that are incapable of chelation to a metal (example:
Cl) also gave excellent enantioselectivity (entry 7). Aliphatic cyclic,
branched or unbranched aldehydes are also acceptable substrates,
affording nitroaldol adducts in good yields and enantioselectivities
˚
Fig. 1 An r.m.s. overlay of Cu, and N atoms (r.m.s. deviation = 0.012 A)
(entries 9–12, 78–90% ee).
21
from X-ray structures of 1 (red) and 2 (blue).
A root-mean-square (r.m.s.) overlay of Cu, and N atoms (r.m.s.
˚
deviation = 0.012 A) of X-ray structures of both catalysts 1 and 2
9,16
are presented in Fig. 1. It is very clear that the conformations of
the (2)-sparteine ligands are nearly identical in both the complexes
as a very good r.m.s. fit was obtained. However, these structures
differ widely in the relative orientation of their counter anions; as a
consequence, significant differences in the bond angles and torsion
environment around the copper(II) site is retained in the solution-
10b
state as well. Thus, the nature of the copper(II) site differs widely
from each other even though ligand conformation is retained in
these complexes. These differences may partly explain the
differences that are experimentally observed in their catalytic
activities and selectivities in the asymmetric Henry reaction.
In conclusion, we have shown that dichloro[(2)-sparteine-
N,N9]copper(II) is an effective catalyst for asymmetric Henry
reaction of nitromethane with various structurally divergent
aldehydes. In general, high enantioselectivities were obtained for
9
angles (15 to 20 degrees) around the copper(II) site were observed.
X-ray analysis also showed the copper(II) site is distorted in both
the complexes, however, such a distortion is much more severe in
9,17
catalyst 2 than in catalyst 1.
Both ESR and optical spectral
studies on 2 strongly indicate that the solid-state coordination
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068 | Chem. Commun., 2006, 4066–4068
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