C1-Symmetric 1,2-Diaminobicyclo[2.2.2]octane Ligands in Copper-Catalyzed Asymmetric Henry Reaction: Catalyst Development and DFT Studies

Article abstract of DOI:10.1002/ejoc.201701452

Chiral tetra- and bidentate ligands derived from the (R)-1,2-diaminobicyclo[2.2.2]octane scaffold were synthesized, and the influence of the N,N′-substituents of the ligand on the catalytic activity of their corresponding copper(II) complexes toward the n

Full text of DOI:10.1002/ejoc.201701452

A Journal of
Accepted Article
Title: C1-Symmetric 1,2-diaminobicyclo[2.2.2]octane ligands in Copper-
catalyzed asymmetric Henry Reaction: catalyst development and
DFT studies
Authors: Monique Calmes, Pierre Milbéo, Laure Moulat, Claude
Didierjean, Emmanuel Aubert, and Jean Martinez
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701452
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701452
Supported by

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
C1-Symmetric 1,2-diaminobicyclo[2.2.2]octane ligands in Copper-
catalyzed asymmetric Henry Reaction: catalyst development and
DFT studies
Pierre Milbeo,[a] Laure Moulat,[a] Claude Didierjean,[b] Emmanuel Aubert,[b] Jean Martinez,[a] Monique
Calmès*[a]
Abstract: New chiral tetra- and bidentate ligands derived from the
(R)-1,2-diaminobicyclo[2.2.2]octane scaffold have been synthesized
and the influence of ligand N,N’-substituents on the catalytic activity
of their corresponding copper(II) complexes toward nitroaldol
reaction have been investigated. Among them, the complex
generated in situ by the interaction of the (R)-N,N’-Bis(1-
naphthylmethyl)-1,2-diaminobicyclo[2.2.2]octane ligand L10 with
Cu(OAc)2 proved to be the most effective for the asymmetric Henry
reaction of nitromethane with various aldehydes, providing -
nitroalcohols in moderate to good yields, and enantioselectivity (up
to 86%). In an attempt to rationalize the factors that control
enantiodifferentiation, the most stable geometries of this C1-
symmetric bicyclic copper ligand complex, as well as plausible
transition structures of the nitroaldol reaction, were investigated by
DFT calculations.
ligands based on unsymmetrical substitutions of previously
described scaffolds[2f,8b,8d,8h,8n,8o] and on natural[8a,8g] and new
synthetic systems,[8c,8e,f,8i-m,8p] have also proved to be effective in
the copper-catalyzed Henry reaction. To synthesize efficient C1-
symmetric catalysts that do not possess any symmetry axis
reducing the possible diastereoisomeric reaction pathways, it is
important to focus on electronic and steric controlling factors in
the design of new ligands.
Results and Discussion
We recently reported on the synthesis of a bicyclic C1-symmetric
chiral 1,2-diamine [(R)-DABO], containing a bicyclo[2.2.2]octane
motif with one amine function at the bridgehead position.[9] This
bridged bicyclic skeleton was recently proved to highly restrict
the conformation of (R) and (S)-1-aminobicyclo[2.2.2]octane-2-
carboxylic acid (ABOC) useful as potent helix inducers in homo-
and mixed oligoureas,[10a] and in 1:1 or 2:1 ,-hybrid
peptides,[10b,c] or as part of ,-peptide organocatalysts used in
asymmetric aldol reactions.[11] Considering the significance of
steric factors in chiral catalyst systems based on C1-symmetric
ligands, and the high constraint capacity of DABO, we
investigated a series of its copper-diamine ligand derivatives for
the asymmetric Henry reaction.
Introduction
Chiral diamine ligands are widely used as catalyst precursors for
quite
a
number of transition-metal-catalyzed asymmetric
transformations.[1] Among them, the use of chiral copper
complexes with chiral tetradentate and bidentate ligands have
proven to be one of the most effective in the asymmetric
nitroaldol (Henry) reaction of aldehydes with nitroalkanes.[2] This
reaction provides the elaboration of polyfunctionalized chiral
molecules. In particular, the resulting nitroaldol adducts
constituted attractive building blocks to generate vicinal amino
alcohol motifs often included in many natural or synthetic
complex compounds.[3,4] Since the pioneering work of Shibasaki
in 1992,[5] several studies on the asymmetric copper-catalyzed
Henry reaction have focused on the development of chiral C2-
symmetric ligands that have often proved to possess an
Scheme 1. Synthesis of the 1,2-diaminobicyclo[2.2.2]octane ligands L1-L4.
excellent
stereoselectivities have been obtained using BOX-type,[6a,b,m]
tetrahydrosalen and
(salan),[4d,6c,6h,i] diamines[6d,e,6j,k]
asymmetric
induction
ability.[6]
Thus,
high
Synthesis of DABO tetradentate ligands, and their use in the
Cu-catalyzed asymmetric Henry reaction. We first considered
(R)-DABO as a potential precursor of chiral tetradentate ligands
for the synthesis of copper salen and salan complexes. Chiral
L1 and L2 salen ligands were prepared by condensation of the
diacetate salt of (R)-DABO with either 3,5-di-tert-butyl-2-
hydroxybenzaldehyde or 2-hydroxybenzaldehyde respectively,
in an ethanol/water potassium carbonate solution (Scheme 1,
Figure 1). Suitable crystal obtained in ethanol by slow
evaporation allowed characterization of the L1 ligand structure
by X-ray analysis (Figure S1). Reduction of L1 and L2 Schiff
bases with sodium borohydride yielded the two corresponding
L3 and L4 salan ligands (Scheme 1, Figure 1).
aminosulfonamide[6f,g] C2-symmetric ligands, for example. Some
catalytic systems based on other transition metals, such as Co-
and Cr-complexes have also been developed inducing moderate
to high stereoselectivity.[7] More recently chiral C1-symmetric
[a]
[b]
P. Milbéo, L. Moulat, Prof. J. Martinez, Dr. M. Calmès,
IBMM, UMR 5247 CNRS-Université Montpellier-ENSCM,
Montpellier, France - E-mail: monique.calmes@univ-montp2.fr,
Homepage: http://www.ibmm.univ-montp1.fr
Dr. C. Didierjean, Dr. E. Aubert Université de Lorraine, CNRS,
CRM2, Nancy, France
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
conversion was obtained in all cases after 4-7 days (Table 1,
entries 5-8). However, the use of the preformed copper complex
and the presence of t-butyl groups on the salan aromatic ring,
were essential to afford an acceptable enantioselectivity (Table
1, entry 6). A similar superiority of copper salan catalysts over
their corresponding salen derivatives in terms of both the
conversion rate and the stereoselectivity has already been
described,4d,6c,6h,i and has been rationalized in terms of increased
N-basicity and backbone flexibility around the copper, favouring
the reaction rate and the induction ability. Optimization of the
reaction conditions has been investigated using the most
efficient L3-Cu complex (Table 2). The use of isopropanol
instead of toluene at room temperature induced an increase in
the selectivity of the reaction without increasing the reaction rate
(Table 2, entry 1) that prevented the use of a lower temperature.
At 45°C, although the reaction rate was improved, the induced
stereoselectivity was strongly affected. The reaction rate was
also improved by adding a small amount of organic base to the
reaction mixture. However, under these conditions, no increase
in stereoselectivity was observed (Table 2, entries 3-4) except
when using the weak tertiary N-methyl morpholine base. In this
case, the stereoselectivity was slightly increased (Table 2, entry
5). When the toluene complex of copper(I) triflate[12] was used
for the in situ generation of the chiral copper catalyst, a
deleterious effect on the reaction rate without any enhancement
of the stereoselectivity was observed, affording the nitroaldol
product in only 17-25% yield with a moderate enantioselectivity
after 14 days (Table 2, entries 6 and 7).
Figure 1. Tetradentate ligands L1-L4.
In first attempts, we selected as the model reaction the Henry
reaction of 4-nitrobenzaldehyde with nitromethane, at room
temperature, to investigate the potential of L1-L4 ligands using
either in situ formation of the copper-ligand complex in methanol
or the preformed stable Copper complex in toluene (Table 1).
Stable copper(II) salen and salan complexes (L1-Cu, L2-Cu, L3-
Cu and L4-Cu) were obtained after treatment of L1-L4 ligands
with copper(II) acetate in refluxing methanol. A crystal structure
of the L1-Cu complex was obtained that revealed the almost
planar structure of the aromatic rings with the expected square
planar geometry around the copper center (Figures S2 and S3).
Table 1. Tetradentate ligand’s evaluation in the Henry reaction.
Entry
Catalyst
Solvent
MeOH
Time (d)[b]
Yield[c](%)
ee (%)[d]
1
2
3
4
5
6
7
8
L1+Cu(OAc)2
L1-Cu
10[e]
10[e]
10[e]
10[e]
5
13
16
60
58
68
60
80
78
0
Toluene
MeOH
0
L2+Cu(OAc)2
L2-Cu
0
Toluene
MeOH
0
L3+Cu(OAc)2
L3-Cu
0
Toluene
MeOH
7
60
0
L4+Cu(OAc)2
L4-Cu
4
Toluene
6
5
[a] Reactions were carried out on a 0.15 mmol scale of 4-nitrobenzaldehyde
with 10 equiv of nitromethane at room temperature, and 10 mol % of copper
salt. [b] The reaction time corresponds to complete conversion, except
mention note e. [c] Isolated yield. [d] Enantiomeric excess was determined by
chiral HPLC (OD-H, see SI). [e] Incomplete conversion.
Among the L1-L4 copper complexes, only the preformed L3-Cu
complex was found as a potential catalyst for the asymmetric
Henry reaction (Table 1, entry 6). Indeed, when using the L1-L2
salen ligands, an incomplete conversion was observed even
after 10 days, with formation of the racemic nitroaldol product in
all cases (Table 1, entries 2-4). For L3-L4 salan ligands, a full
Figure 2. Bidentate ligands L5-L12.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
Table 2. Effect of solvent and base in the asymmetric Henry reaction catalysed by L3-Cu or L3+(CuOTf)2.Tol.
Entry
Catalyst
Base
Solvent
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
MeOH
T (°C)
RT
Time (d)[b]
Yield[c] (%)
ee (%)[d]
1
2
3
4
5
6
7
L3-Cu
-
7
88
82
60
81
73
25
17
69
12
56
60
70
60
60
L3-Cu
-
45°C
RT
2
L3-Cu
Py 0,1 mol%
7
L3-Cu
Py 1 mol%
RT
3
L3-Cu
NMM 0.5 mol%
RT
4
L3+(CuOTf)2.Tol
L3+(CuOTf)2.Tol
-
-
RT
14[e]
14[e]
45°C
[a], [b], [c], [d] and [e] see Table 1 (notes a, b, c, d and e respectively).
and 3). A comparison between complexes derived from L7 and
L8 ligands also demonstrated that a bulkier ortho substituent,
led to a slower reaction rate without improving stereoselectivity
(Table 3, entries 3 and 4). Introduction of heteroaromatic
moieties (ligand L9), resulting in two additional heteroatoms
close to the metal in the complex without adding steric
constraints, had a beneficial effect since a total conversion was
observed after 12 hours with a slightly increased enantiomeric
excess (Table 3, entry 5). In terms of enantioselectivity, the best
result was obtained when the L10 ligand copper-complex was
used as catalyst (Table 3, entry 6). The two fused aromatic
pendants of L10 appeared to play an important positive role in
the transition state complex, which was not the case when using
the two L11 and L12 ligands that also possess fused aromatic
rings (Table 3, entries 7 and 8).
Synthesis of DABO bidentate ligands, and their used in the
Cu-catalyzed asymmetric Henry reaction. The first moderate
results of this study, and the previous successful application of
bidentate diamine ligands in the copper catalyzed asymmetric
Henry reaction,[6d,6i,j,8i,8h-j,8l,m] prompted us to investigated the
preparation of bidentate ligands using (R)-DABO and various
ortho-, meta- or para-monosubstituted aromatic moieties, as well
as hetero or fused aromatic moieties (Figure 2).
Scheme 2. Synthesis of the 1,2-diaminobicyclo[2.2.2]octane ligands L5-L12.
Table 3. Bidentate ligand’s evaluation in the asymmetric Henry reaction.
Compounds L5-L12 were easily prepared by
a two-step
synthesis starting from (R)-DABO diacetate and the selected
aldehyde, without isolation of the diimine intermediates (Scheme
2). L5-L12 ligand complexes with Cu(OAc)2 generated in situ
were evaluated in the Henry reaction of 4-nitrobenzaldehyde
with nitromethane, in i-PrOH at 0°C, to define the influence of
both the electronic nature and the size of the aromatic moieties
in the diamine ligands (Table 3). As a general remark, L5-L12
ligand copper complexes were globally more efficient catalysts
than the previously tested complexes derived from L1-L4
ligands, in terms of yield and induced stereoselectivity of the
Henry reaction. Among them, L5 ligand with a para-chloro
substituent on the aromatic moiety allowed a large increased in
the reaction rate (Table 3, entry 1). On the other hand, when the
chlorine atom was closer to the copper, in both meta or ortho-
position of the aromatic moiety increasing the steric hindrance
around the metal, the stereoselectivity was slightly increased
with however a decrease of the reaction rate (Table 3, entries 2
Entry
Ligand
Time (h)[b]
Yield[c](%)
ee (%)[d]
1
2
3
4
5
6
7
8
L5
7
66
50
78
72
77
95
74
66
50
56
64
64
72
80
64
30
L6
48e
60
240
12
72
60
48e
L7
L8
L9
L10
L11
L12
[a], [b], [c], [d] and [e] see Table 1 (notes a, b, c, d and e respectively).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
Table 4. Effect of solvents and bases in the asymmetric Henry reaction catalysed by L10/Cu(OAc)2.
Entry
1
Solvent
EtOH
T (°C)
Time (h)[b]
Yield[c] (%)
ee (%)[d]
60
rt
0
rt
0
0
rt
0
0
0
0
0
1.5
36
12
72
24
2
81
77
90
95
67
80
70
72
70
60
20
2
EtOH
42
3
i-PrOH
i-PrOH
n-BuOH
t-BuOH
Toluene
CH2Cl2
THF
68
4
80
5
33
6
68
7
72
96
96
96
168[e]
52
8
50
9
75
10
11
CH3CN
Et2O
42
70
[a], [b], [c], [d] and [e] see Table 1 notes a, b, c, d and e respectively.
Optimization of the experimental reaction conditions. To find
optimized reaction conditions using the most efficient chiral L10
ligand, several experiments were carried out involving
modification of the solvent, the reaction temperature, the copper
salt, and testing various base additives. The different tested
alcohols (EtOH, i-PrOH, t-BuOH) as solvents afforded good
yields and comparable enantiomeric excesses when the reaction
was performed at room temperature (Table 4, entries 1, 3 and 6).
Lowering the temperature to 0° C, linear alcohols such as EtOH
and n-BuOH resulted in a decrease in both the reaction rate, the
stereoselectivity and the yield (Table 4, entries 2 and 5). When
the reaction was carried out in aprotic solvents, at 0 °C,
moderate enantioselectivities and yields were generally obtained
that could be mostly compared to linear alcohols. It can be noted
furthermore that higher enantioselectivities were observed when
using oxygenated aprotic solvent such as THF and diethyl ether
(Table 4, entries 9 and 11). Finally, branched i-PrOH proved to
be the most suitable solvent at 0 ° C for this reaction.
changing the solvent, the temperature and by using organic
bases as additives, the enantiomeric excess obtained was
always lower than when obtained using copper acetate (Table 5,
entries 6-15). Finally, the use of copper(I) salts, such as CuCl or
(CuOTf)2.tol, only afforded the racemic nitroaldol product (Table
5, entries 16 and 17).
Aldehyde scope of the L10/Cu(OAC)2 system. On the basis of
the optimized reaction parameters, the L10-Cu(OAc)2 catalyst
was then applied to the enantioselective Henry reaction using
various aromatic aldehydes and nitromethane (Table 6). The
first general observation was that both the conversion rate and
the enantioselectivity were dependent on electronic and steric
properties of the substituents on the aldehyde aromatic ring. The
reaction of nitromethane with benzaldehydes bearing one
electron-withdrawing substituent in 2- and 3-position proceeded
faster than with benzaldehyde substituted in 4-position (Table 6,
entries 2, 4-8). In term of stereoselectivity, divergent results
were observed depending on the nature/position of the electron-
withdrawing substituent. Higher enantiomeric excesses were
obtained with the 2- and 4-nitro substituted aldehydes (Table 6,
entries 2, 3 and 5) while the best results were obtained with the
3- and 4-chloro derivatives (Table 6, entries 7 and 8). The use of
4-trifluorobenzaldehyde led to the full conversion into the
nitroaldol product faster than the 4-substituted aldehydes but
with a slightly lower enantiomeric excess (Table 6, entry 9).
Curiously, aromatic aldehydes bearing two electron-withdrawing
groups at 2,4- and 3,4-position of aromatic ring did not exhibit
any difference in reactivity yielding both good conversion rates
and enantioselectivities (Table 6, entries 11 and 12).
Several divalent copper salts were then evaluated in
combination with L10 ligand in i-PrOH at 0°C (table 5). The
presence of water in the copper diacetate salt was not beneficial
for the reaction (Table 5, entry 2) and could compare with the
use of the copper acetyl acetonate salt (Table 5, entry 3).
Likewise, copper(II) triflate was not effective affording only 5%
yield after 96 hours (Table 5, entry 4). As a consequence of the
high enantiomeric excess (88% ee) but incomplete conversion
observed when using CuCl2, 2H2O, further optimization of the
reaction conditions have been investigated with this copper salt.
Although improvement in the conversion rate occurred by
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
Table 5. Effect of varying metal ion source, solvent, temperature and base in the asymmetric Henry reaction catalysed by L10.
Entry
1
Copper salt
Cu(OAc)2
Solvent
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
EtOH
Base (mol%)
T (°C)
Time (h)[b]
72
Yield[c] (%)
ee (%)[d]
80
72
60
nd
88
nd
46
44
56
66
70
70
71
52
68
0
-
0
0
0
0
0
rt
rt
rt
rt
rt
rt
0
0
0
0
0
0
95
95
91
5
2
Cu(OAc)2, H2O
Cu(acac)2
-
96
3
-
96
4
Cu(OTf)2
-
96[e]
96[e]
96[e]
84[e]
12
5
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl2, 2H2O
CuCl
-
33
traces
50
75
85
85
87
94
91
82
38
54
23
6
-
7
THF
-
8
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
Pyridine (10)
Pyridine (1)
NMM (10)
NMM (1)
NMM (1)
AcONa (20)
AcONa (10)
AcONa (1)
-
9
12
10
11
12
13
14
15
16
17
12
96
96
48
96
240[e]
12
(CuOTf)2, tol
-
96[e]
0
[a], [b], [c], [d] and [e] see Table 1 (notes a, b, c, d and e respectively).
A drastic decrease in the conversion rate was observed for
aromatic aldehydes bearing electron-donating groups in both
2,4- and 3,5-position, affording incomplete conversion after 96
hours, with low and moderate enantiomeric excess respectively
(Table 6, entries 13 and 14). In an attempt to increase the
stereoselectivity, experiments involving the two most reactive
aldehydes (R = 2-NO2C6H4 and 4-CF3C6H4) were carried out at
lower temperature (-20°C) (Table 6, entries 3 and 10). In these
conditions, full conversion was observed after 60 hours, instead
of 24 hours at 0°C, with no positive effect on the enantiomeric
excess. The Henry reaction of the two 1- or 2-fused aromatic
ring aldehydes with nitromethane resulted in similar reactivity
and stereoselectivity, indicating no significant effect of the steric
hindrance of the substrate (Table 6, entries 15 and 16). Finally,
the reaction of furyl aldehyde and of some aliphatic aldehydes
with nitromethane was investigated under the same
experimental conditions, affording low to moderate yields of the
corresponding nitroaldols, with stereoselectivities in a range of
those of the aromatic analogues (Table 6, entries 17-20).
Interestingly, it can be noted that in all cases investigated in this
study, and using the in situ generated copper (R)-L10 complex,
the nucleophilic addition of the nitromethane proceeded mainly
from the Re face of the aldehydes affording the corresponding
(S) nitro alcohols with moderate to high enantioselectivities (up
to 86%).
DFT calculations. Optimized geometries of the L3-Cu and
L10-Cu(OAc)2 complexes. Suitable crystals of the L3-Cu and
L10-Cu(OAc)2 complexes could not be obtained for X-ray
analysis. However, to gain information about these complexes,
their geometries were optimized at the DFT level of theory by
employing the B3LYP functional[13] (completed with Grimme D3
dispersion correction[14]), and the 6-311G(d,p) basis set. The
optimized L3-Cu conformation (figure S4 A and B) revealed a
non-coplanar position of the aromatic rings, a slightly distorted
square planar geometry around the metal, and an orientation
toward opposite directions of the two NH groups. Compared to
the L1-Cu crystal structure, these structural outcomes showed
that L3-Cu complex possessed a more hindered coordination
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
Table 6. Aldehyde scope of the L10/Cu(OAC)2 system.
Entry
1
R
T (°C)
Time (h)[b]
96
Yield[c] (%)
50
ee (%)[d]
60
C6H5
0
2
2-NO2C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-CF3C6H4
4-CF3C6H4
2,4-diClC6H3
3,4-diClC6H3
2,4-diMeOC6H3
3,5-diMeOC6H3
1-naphtyl
2-naphtyl
2-furyl
0
24
78
82
3
-20
0
60
85
74
4
24
81
50
5
0
72
95
80
6
0
36
66
66
7
0
36
70
84
8
0
96
73
86
9
0
24
82
75
10
11
12
13
14
15
16
17
18
19
20
-20
0
60
74
48
10
87
72
0
10
87
72
0
96[e]
96[e]
96
12
10
0
50
66
0
75
73
0
96
75
69
0
48
62
70
t-Bu
0
48[f]
48[g]
48
45
82
n-hexyl
0
23
80
cyclohexyl
0
75
80
[a], [b], [c], [d] and [e] see Table 1 (notes a, b, c, d and e respectively).
sphere that could be at the origin of the highest observed
selectivity (figure S4 C).
DFT calculation. Stereochemical outcome of the nitroaldol
reaction. To rationalize asymmetric induction transfer from L10
chiral copper complex to the nitroaldol adduct, theoretical
studies of transition structures were also undertaken by means
of DFT calculations. Based on the modelled complex L10-
Cu(OAc)2-6 and on the previously reported steric and electronic
considerations,[6a] various conformations/configurations of L10-
Cu, one acetate group, the 4-nitrobenzaldehyde, and a nitronate
anion, were considered. Various starting geometries leading to
both R and S absolute configurations of the product were
considered.
In the case of L10-Cu(OAc)2, various conformations (Table S2),
were obtained due to the possible orientations of the naphthyl
groups and the positions of the acetate groups. In each case,
these acetate groups were found to be stabilized by hydrogen
bonding with NH hydrogen atoms located in opposite positions,
in addition to their coordination to the metal (Figures S5-S11).
The most stable L10-Cu(OAc)2-6 conformation (Figure S10)
possessed the four atoms around the metal in a slightly
deformed square plane, and the two naphthyl groups located on
both side of the bicycle almost perpendicularly to the square
plane.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
ΔGTS-reac=6.45 kJ.mole-1
ν=-146.08 cm-1
ΔGprod-TS=-47.61 kJ.mole-1
S
ΔGprod-reac=-41.16 kJ.mole-1
Figure 3. Optimized transition structures (reactants, transition state and products) of the L10-Cu(OAc, 4-nitrobenzaldehyde, nitronate anion) complex Cplx5.
NH···O hydrogen bond and contacts, and Caldeh.···CMeNO2 distances are indicated in Å. Most of the hydrogen atoms were omitted for clarity.
As for previous calculations, the B3LYP functional completed
with Grimme D3 dispersion correction[14] was used with the 6-
311G(d,p) basis set. The solvent effects (i-PrOH) were taken
into account through the PCM model.[15] Frequency calculations
confirmed the nature of the transition state (TS), which was
characterized with only one imaginary frequency. Then,
reactants and products were fully optimized starting from the TS
geometry (slightly deformed according to the imaginary
frequency normal mode). Frequency calculations on these last
fully optimized geometry proved that true energy minima were
obtained. Table S3 summarizes the obtained energies and
energy barriers for the optimized transition structures (reactants,
transition state and products) of the L10-Cu(OAc, 4-
nitrobenzaldehyde, nitronate anion) complexes Cplx1-Cplx9.
The four transition state structures having the lowest energy
barriers (Cplx5, Cplx4, Cplx1 and Cplx2; ΔG=6-17kJ.mol-1)
were characterized by the largest Cald.· ··CMeNO2 interatomic
distances (2.2 – 2.3Å), associated to the smallest Cu ·· Oald.
bond distances (1.99 – 2.02 Å) (Tables S4-S6). By comparison,
the other structures, having larger energy barriers (ΔG=28-
63kJ.mol-1), showed these two distances shorter and larger by
about 0.2 – 0.3 Å, respectively. Thus, activation of the aldehyde
carbon atom to favor the C-C bond formation was triggered by
stabilization of the oxygen atom negative charge, and by the
proximity of the latter with the central copper cation. Moreover,
these most stable transition states were also stabilized by
hydrogen bonding involving the NH diamine groups of the L10
ligand, toward the uncoordinated oxygen atoms of the acetate
and nitronate anions (Table S3). More specifically, stabilization
of the nitronate by hydrogen bonding with L10 appeared as a
key characteristic since among the high energy barrier structure
only one had such a hydrogen bond, which is rather long and
thus not so stabilizing (Cplx7; 2.524 Å; 117.2°).
As it can be seen from Table S3, the two most stable reactant
complexes (Cplx7 and Cplx8) were those leading to R products.
However, these two conformations were associated to high-
energy barriers toward the transition states (~45kJ.mol-1) and the
products formed were either destabilised (Cplx8) or moderately
stabilized (Cplx7). The next two most stable reactants, about
10kJ.mol-1 less stable (Cplx2, and Cplx5) led to S products and
were associated to most stable transition states (Cplx5), and
corresponding products were the most stabilized. Thus, the
lowest energy barrier toward transition state was associated to
the S configuration (Cplx5), being only of 6.45kJ.mole-1 (Figures
3 and S13-S18). These calculations supported the preferential
formation of S products with an approach of the nitronate by the
Re face of the aldehyde, in agreement with the experimental
results.
Conclusions
In conclusion, the synthesis of several chiral salen, salan and
diamine
ligands
derived
from
the
1,2-
diaminobicyclo[2.2.2]octane scaffold, as well as the catalytic
activity of their corresponding copper(II) complexes toward the
reaction of nitromethane with various aldehydes, have been
described. It was found that the most efficient catalytic system
involves the N,N’-bis(1-naphthylmethyl)diamine derivative to
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
+205.7°(c = 1.1, CHCl3); 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.24 (s, 18H, 6CH3),
1.38 (s, 9H, 3CH3), 1.42 (s, 9H, 3CH3), 1.71-1.86 (m, 7H, 3CH2 and 4-H), 1.92-2.06
(m, 2H, CH2), 2.20 (m, 2H, CH2), 3.59 (d, J = 8.9 Hz, 1H, 2-H), 7.00 (dd, J = 7.3 Hz
and 2.3 Hz, 2H, Ar-H), 7.30 (dd, J = 7.9 Hz and 2.3 Hz, 2H, Ar-H), 8.23 (s, 1H, 1-
N=CH), 8.29 (s, 1H, 2-N=CH); 13C NMR (100 MHz, CDCl3): δ (ppm) = 24.9 (CH2),
25.1 (4-CH), 26.1 and 26.3 (CH2), 29.6 and 31.6 (CH3), 32.6 (CH2), 34.2 and 35.1
(tBu-C), 36.3 (CH2), 60.1 (1-C), 71.4 (2-CH), 118.0 and 118.2 (Ar-C), 126.2 and
126.9 (Ar-CH), 136.4 and 140.0 (Ar-CtBu), 158.1 and 158.6 (Ar-COH), 163.1 and
165.9 (N=CH); HRMS (ESI-TOF) m/z [M+H]+ calcd. for C38H57N2O2 573.4420,
found. 573.4422.
afford the corresponding -nitroalcohols in moderate to good
yield and enantioselectivity. In agreement with the experimental
results, DFT calculations support the preferential formation of
the S product with transfer of the nitronate anion to the Re face
of the aldehyde.
Experimental Section
(R)-Bis(2-hydroxybenzylidene)-1,2-diaminobicyclo[2.2.2]octane
L2
was
obtained from 2-hydroxybenzaldehyde as yellow crystals in 80% yield according
General experimental details, analytical data of nitroalcohol adducts, copies of
1H, 13C NMR spectra and HRMS analysis can be found in the Supporting
Information, as well as Tables and Figures of DFT structural calculations. CCDC
1577508-1577509 contain the crystal structures of L1 and L1-Cu. Data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
25
to the general procedure A. M.p. 88-90 °C; [α]D = +4.2°(c = 1.2, CHCl3); 1H
NMR (400 MHz, CDCl3): δ (ppm) = 1.63-2.01 (m, 9H, 3CH2, HCH, 4-CH, 3-HCH);
2.15-2.26 (m, 2H, HCH, 3-HCH), 3.56, (m, 1H, 2-CH), 6.75-6.91 (m, 4H, Ar-H),
7.12-7.28 (m, 4H, Ar-H), 8.18 (s, 1H, 1-N=CH), 8.22 (s, 1H, 2-N=CH); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 24.6 (CH2), 25.0 (4-CH), 26.0, 26.1 and 32.5 (CH2),
36.3 (3-CH2), 60.4 (1-C), 71.4 (2-CH), 116.9, 117.1 and 118.5 (Ar-CH), 118.8 and
118.9 (Ar-CH, Ar-C), 131.7 and 132.3 (Ar-CH), 161.2 and 161.6 (Ar-COH), 162.0
and 164.5 (N=CH), HRMS (ESI-TOF) m/z [M+H]+ calcd. for C22H25N2O2 349.1916,
found 349.1913.
General procedure A for the synthesis of Schiff bases L1 and L2 (R)-1,2-
diaminobicyclo[2.2.2]octane diacetate (R)-DABO (1 eq., 100 mg, 0.38 mmol)
and potassium carbonate (2 eq., 106 mg, 0.76 mmol) were dissolved in a
mixture of distilled water and ethanol (H2O/EtOH : 0.6/2 mL), and the mixture
was heated to reflux. A solution of the aldehyde (2 eq., 0.76 mmol) in ethanol
(1 mL) was added dropwise with a syringe, and the mixture was stirred at reflux
for 2 hours. The reaction was then cooled to 0°C and quenched with cold
distilled water, leading to precipitation of the product. The precipitate was
filtered and washed with cold ethanol to give the corresponding Schiff bases.
(R)-N,N’-Bis(3,5-di-tert-butyl-2-hydroxybenzy)-1,2-
diaminobicyclo[2.2.2]octane L3 was obtained from 3,5-Di-tert-butyl-2-
hydroxybenzaldehyde as a colourless oil in 81% yield according to the general
procedure D. tR (HPLC) column A, gradient A = 3.50 min; MS (ESI): m/z = 219.32
[4-ditertbutyl-6-methylphenol+H]+,
359.3
[M-(2,4-di-tert-butyl-6-
methylphenol)+H]+, 577.3 [M+H]+; [α]D = -10.4°(c = 1.5, CHCl3); 1H NMR (400
MHz, CDCl3): δ (ppm) = 1.27 and 1.29 (2s, 18H, 6CH3), 1.39 (s, 18H, 6CH3), 1.64-
1.75 (m, 10H, 4CH2, 4-CH, 3-HCH), 2.02 (m, 1H, 3-HCH), 2.95 (s, 1H, 2-CH), 3.92-
3.75 (m, 3H, CH2N, HCHN), 4.08 (d, J = 13.2 Hz, 1H, HCHN), 6.90 (br d, J = 2.4 Hz,
2H, Ar-H), 7.21 (br d, J = 2.4 Hz, 1H, Ar-H), 7.25 (m, 1H, Ar-H); 13C NMR (100
MHz, CDCl3): δ (ppm) = 24.5 (4-CH), 25.6, 26.0, 26.2 and 29.1 (CH2), 29.7 (CH3),
31.7 (CH3), 34.2 (3-CH2), 34.9 and 35.0 (C-tBu), 45.5 (1-NCH2), 51.0 (2-NCH2),
53.6 (1-C), 55.8 (2-CH), 122.9, 123.0 and 123.2 (Ar-CH), 136.2 (Ar-C), 140.8 (Ar-
CtBu), 154.4 (Ar-COH); HRMS (ESI-TOF) m/z [M+H]+ calcd. for C38H61N2O2
577.4733, found 577.4739.
25
General procedure B for the synthesis of preformed copper complex L1-Cu,
L2-Cu
The ligand (L1 or L2) (1 eq., 0.018 mmol) was dissolved in methanol (2 mL).
Copper diacetate (2 eq., 6.4 mg, 0.036 mmol) was added, and the solution was
heated to reflux for 15 hours. The solution was concentrated under reduced
pressure, dissolved with CH2Cl2 and filtered. The filtrate was concentrated
under reduced pressure to give the corresponding copper complex.
General procedure C for the synthesis of preformed copper complex L3-Cu
and L4-Cu
(R)-N,N’-Bis(2-hydroxybenzyl)-1,2-diaminobicyclo[2.2.2]octane
L4
was
The ligand (L3 or L4) (1eq., 0.07 mmol) was dissolved in ethanol (2 mL). Copper
diacetate (2 eq., 12.4 mg, 0.14 mmol) was added, and the solution was stirred
at room temperature overnight. The solution was concentrated under reduced
pressure and the crude was purified by column chromatography on silica gel
(elution gradient CH2Cl2 to CH2Cl2/MeOH, 8:2) yielding the expected copper
complex.
obtained from 2-hydroxybenzaldehyde as a colourless oil in 66% yield according
to the general procedure D. tR (HPLC) column A, gradient A = 1.84 min; MS (ESI):
m/z =141.3 [M-2(2-methylphenol)+H]+, 247.2 [M-(2-methylphenol)+H]+, 353.2
25
[M+H]+; [α]D = -24.1°(c = 1.2, CHCl3); 1H NMR (400 MHz, CDCl3): δ (ppm) =
1.60-1.74 (m, 10H, 4 CH2, 3-HCH, 4-CH); 2.00 (t, J1 = J2 = 11.4 Hz, 1H, 3-HCH),
2.85 (d, J = 9.4 Hz, 1H, 2-CH), 3.72 (d, J = 13.7 Hz, 1H, 2-NHCH), 3.76 (d, J = 13.9
Hz, 1H, 1-NHCH), 3.85 (d, J = 13.9 Hz, 1H, 1-NHCH), 4.11 (d, J = 13.7 Hz, 1H, 2-
NHCH), 6.75-6.87 (m, 4H, Ar-H), 6.95 (d, J = 7.0 Hz, 1H, Ar-H), 7.01 (d, J = 7.0 Hz,
1H, Ar-H), 7.13-7.21 (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): δ (ppm) =24.5 (4-
CH), 25.7, 26.0, 26.4 and 29.1 (CH2), 34.8 (3-CH2), 44.9 (N-CH2), 49.8 (N-CH2),
53.8 (1-C), 55.4 (2-CH), 116.6, 116.7 and 119.4 (Ar-CH), 122.8, 123.6 (Ar-C),
128.4, 128.8, 128.9 and 129.2 (Ar-CH), 158.0 and 158.1 (Ar-COH); HRMS (ESI-
TOF) m/z [M+H]+ calcd. for C22H29N2O2 353.2229, found 353.2227.
General procedure D for the synthesis of ligands L3-L12
(R)-1,2-diaminobicyclo[2.2.2]octane diacetate (R)-DABO (1 eq., 40 mg, 0.15
mmol) and potassium carbonate (2 eq., 42.5 mg, 0.30 mmol) were dissolved in
distilled water (0.2 mL), and ethanol (0.6 mL) was added. The mixture was
heated to reflux. A solution of aldehyde (2 eq.) in ethanol (0.75 M) was added
dropwise with a syringe and the mixture was stirred at reflux for 12 hours. The
reaction was then cooled to 0°C, diluted with CH2Cl2 and quenched with cold
distilled water. The product was extracted with CH2Cl2, the combined organic
layers were washed with water, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude was then dissolved in methanol (2 mL) at 0
°C. NaBH4 (3 eq., 17.6 mg, 45 mmol) was added to the reaction mixture in 3
portions (1 every 10 min). Stirring at this temperature was maintained until gas
evaporation was stopped and the mixture was allowed to reach room
temperature. After complete conversion monitored by HPLC, the reaction
media was quenched with distilled water, and all the volatiles were evaporated.
The resulting aqueous mixture was extracted with CH2Cl2 and the combined
organic layers were dried over MgSO4, filtered and concentrated in vacuo. The
resulting crude was purified by column chromatography on silica gel (elution
gradient CH2Cl2 to CH2Cl2/MeOH, 95:5) yielding the expected ligand.
Preformed copper complex L1-Cu was obtained as black cube shape crystals
after recrystallization from CH2Cl2/MeOH (10 mg, 90 % yield) following the
general procedure B. M.p. >200 °C; MS (ASAP): m/z = 634.36 [M+H]+; FT-IR
(neat) : 2943, 2905, 2864, 1608, 1525, 1463, 1423, 1384, 1357, 1328, 1253,
1169, 1077, 1021, 811, 788, 742.
Preformed copper complex L2-Cu was obtained as a purple powder (7 mg, 95%
yield) following the general procedure B. M.p. >200 °C; MS (ASAP): m/z =
410.11 [M+H]+; FT-IR (neat) : 2926, 2913, 2864, 1611, 1600, 1531, 1443, 1387,
1346, 1321, 1201, 1142, 1066, 1030, 909, 849, 751, 736.
Preformed copper complex L3-Cu was obtained as a dark green solid (44 mg,
quant.) following the general procedure C. M.p. >200 °C; MS (ASAP): m/z =
638.36 [M+H]+; FT-IR (neat) : 2945, 2901, 2863, 1618, 1461, 1437, 1412, 1358,
1296, 1262, 1234, 1199, 1168, 872, 827, 735.
(R)-Bis(3,5-di-tert-butyl-2-hydroxybenzylidene)-1,2-
diaminobicyclo[2.2.2]octane L1 was obtained from 3,5-Di-tert-butyl-2-
hydroxybenzaldehyde as yellow crystals in 91% yield according to the general
25
procedure A. M.p. 176-178 °C; MS (ASAP): m/z = 573.4 [M+H]+; [α]D
=
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
Preformed copper complex L4-Cu was obtained as a dark green solid following
the general procedure C. M.p. >200 °C; MS (ASAP): m/z = 414.11 [M+H]+; FT-IR
(neat) : 2920, 2863, 1597, 1562, 1481, 1446, 1394, 1256, 1111, 1011, 877, 755.
3.62 (d, J = 14.4 Hz, 1H, 2-NHCH), 3.80 (d, J = 14.4 Hz, 1H, 2-NHCH), 6.15 (m, 1H,
Ar-H), 6.21 (m, 1H, Ar-H), 6.33 (m, 2H, Ar-H), 7.39 (m, 2H, Ar-H); 13C NMR (100
MHz, CD3CN): δ (ppm) = 25.7 (4-CH), 26.8, 26.9, 27.1 and 29.8 (CH2), 35.5 (3-
CH2), 38.9 (1-NCH2), 44.1 (2-NCH2), 53.6 (1-C), 55.5 (2-CH), 107.0, 107.9, 111.2
and 111.3 (=CH), 142.6 and 142.8 (=CH-O), 155.6 and 156.3 (=C-O); HRMS (ESI-
TOF) m/z [M+H]+ calcd. for C18H25N2O2 301.1916, found. 301.1917.
(R)-N,N’-Bis(4-chlorobenzyl)-1,2-diaminobicyclo[2.2.2]octane L5 was obtained
from 4-chlorobenzaldehyde as a colourless oil in 66% yield according to the
general procedure D. tR (HPLC) column A, gradient A = 2.50 min; MS (ESI): m/z =
265.3 [M-(4-chlorotoluene)+H]+, 389.3 [M+H]+; [α]D25 = -16.9°(c = 1.3, CHCl3); 1H
NMR (400 MHz, CDCl3): δ (ppm) = 1.34-1.40 (m, 1H, HCH), 1.48-1.51 (m, 1H, 3-
HCH), 1.56-1.78 (m, 8H, HCH, 4-CH, 3CH2), 1.87-1.92 (m, 1H, 3-HCH), 2.15 (br.s,
2H, 2NH), 2.64 (m, 1H, 2-CH), 3.36 (d, J = 13.0 Hz, 1H, 1-NHCH), 3.56 (d, J = 13.6
Hz, 1H, 2-NHCH), 3.57 (d, J = 13.0 Hz, 1H, 1-NHCH), 3.88 (d, J = 13.6 Hz, 1H, 2-
NHCH), 7.19-7.28 (m, 8H, Ar-H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 24.8 (4-
CH), 26.3, 26.4, 26.8 and 29.7 (CH2), 35.3 (3-CH2), 44.9 (1-NCH2), 50.5 (2-NCH2),
53.2 (1-C), 54.9 (2-CH), 128.6, 129.4 and 129.8 (Ar-CH), 132.6 and 132.7 (Ar-
CCl), 139.3 and 139.8 (Ar-C); HRMS (ESI-TOF) m/z [M+H]+ calcd. for C22H27N2Cl2
389.1551, found. 389.1552.
(R)-N,N’-Bis(1-naphthylmethyl)-1,2-diaminobicyclo[2.2.2]octane L10 was
obtained from 1-naphthaldehyde as a colourless oil in 97% yield according to
the general procedure D. tR (HPLC) column A, gradient A = 2.75 min; MS (ESI):
m/z = 141.1 [M-(2 methylnaphtalene)+H]+, 281.3 [M-(methylnaphthalene)+H]+,
421.1 [M+H]+; [α]D25 = -3.1°(c = 1.3, CHCl3); 1H NMR (400 MHz, CD3CN): δ (ppm)
=1.43-1.51 (m, 1H, HCH), 1.59-1.77 (m, 7H, HCH, 3CH2, 3-HCH, 4-CH), 2.06 (m,
1H, 3-HCH), 2.90 (m, 1H, 2-CH), 3.76 (d, J = 12.7 Hz, 1H,1-NHCH), 3.96 (d, J =
13.1 Hz, 1H,2-NHCH), 4.01 (d, J = 12.7 Hz, 1H, 1-NHCH), 4.39 (d, J = 13.1 Hz, 1H,
2-NHCH), 7.19 (d, J = 7.5 Hz, 1H, Ar-H), 7.26 (ddd, J = 8.3 Hz, 6.8 Hz and 1.3 Hz,
1H, Ar-H) 7.31-7.45 (m, 6H, Ar-H), 7.74 (t, J = 7.5 Hz, 2H, Ar-H), 7.83 (t, J = 8.3
Hz, 2H, Ar-H), 7.99 (d, J = 8.8 Hz, 1H, Ar-H), 8.14 (d, J = 8.3 Hz, 1H, Ar-H); 13C
NMR (100 MHz, CD3CN): δ (ppm) = 25.9 (4-CH), 27.0, 27.2, 30.0 and 30.4 (CH2),
35.9 (3-CH2), 43.6 (1-NCH2), 49.8 (2-NCH2), 54.2 (1-C), 57.0 (2-CH), 125.0, 125.2,
126.4, 126.5, 126.8, 126.9, 127.4, 128.2, 128.4 and 129.4 (Ar-CH), 132.8, 132.9,
134.8, 134.9, 137.7,and 138.1 (Ar-C); HRMS (ESI-TOF) m/z [M+H]+ calcd. for
C30H33N2 421.2644, found 421.2638.
(R)-N,N’-Bis(3-chlorobenzyl)-1,2-diaminobicyclo[2.2.2]octane L6 was obtained
from 3-chlorobenzaldehyde as a colourless oil in 81% yield according to the
general procedure D. tR (HPLC) column A, gradient A = 2.49 min; MS (ESI): m/z =
265.2 [M-(4-chlorotoluene)+H]+, 389.1 [M+H]+;
25
[α]D = -14.2°(c = 1.3, CHCl3) ; 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.38-1.80
(m, 10H, 4CH2, 3-HCH, 4-CH), 1.89-1.95 (m, 1H, 3- HCH), 2.02 (br.s, 2H, 2NH),
2.68 (m, 1H, 2-CH), 3.38(d, J1 = 13.8 Hz, 1H, 1-NHCH), 3.60 (d, J1 = J2 = 13.8 Hz,
2H, 1-NHCH, 2-NHCH), 3.93 (d, J2 = 13.8 Hz, 1H, 2-NHCH), 7.15-7.25 (m, 6H, Ar-
H), 7.28 (s, 1H Ar-H), 7.30 (s, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δ (ppm) =
24.8 (4-CH), 26.3, 26.7 and 29.6 (CH2), 35.0 (3-CH2), 45.1(1-NCH2), 50.6 (2-
NCH2), 53.4 (1-C), 54.9 (2-CH), 126.3, 126.7, 127.2, 127.3, 128.3, 128.6, and
129.8 (Ar-CH), 134.4 (Ar-CCl),142.5 and 143.1 (Ar-C); HRMS (ESI-TOF) m/z
[M+H]+ calcd. for C22H27N2Cl2 389.1551, found. 389.1552
(R)-N,N’-Bis(2-naphthylmethyl)-1,2-diaminobicyclo[2.2.2]octane L11 was
obtained from 2-naphthaldehyde as a white solid in 77% yield according to the
general procedure D. M.p. 130-132 °C; tR (HPLC) column A, gradient A = 2.86
min; MS (ESI): m/z
=
141.1 [M-(2 methylnaphtalene)+H]+, 281.2 [M-
(methylnaphthalene)+H]+, 421.3 [M+H]+; [α]D25 = +37.6°(c = 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3): δ (ppm) = 1.49-1.74 (m, 8H, 3CH2, 4-CH, 3-HCH), 1.83 (m, 1H,
HCH), 1.91-2.00 (m, 2H, HCH, 3-HCH), 2.83 (m, 1H, 2-CH), 3.53 (d, J = 12.9 Hz,
1H, 1-NHCH), 3.75 (d, J = 12.9 Hz, 1H, 1-NHCH), 3.84 (d, J = 13.6 Hz, 1H, 2-
NHCH), 3.94 (br s, 2H, NH), 4.19 (d, J = 13.6 Hz, 1H, 2-NHCH), 7.39-7.47 (m, 6H,
Ar-H), 7.66-7.79 (m, 8H, Ar-H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 24.6 (4-
CH), 26.0, 26.1, 26.4 and 29.1 (CH2), 34.1 (3-CH2), 45.5 (1-NCH2), 50.7 (2-NCH2),
54.1 (1-C), 54.3 (2-CH), 125.8, 126.0, 126.1, 126.3, 126.8, 126.9, 127.5, 127.7,
127.8, 127.9, 128.2 and 128.5 (Ar-CH), 132.8, 132.9, 133.4, 133.5, 135.9 and
136.9 (Ar-C); HRMS (ESI-TOF) m/z [M+H]+ calcd. for C30H33N2 421.2644, found
421.2645.
(R)-N,N’-Bis(2-chlorobenzyl)-1,2-diaminobicyclo[2.2.2]octane L7 was obtained
from 2-chlorobenzaldehyde as a colourless oil in 84% yield according to the
general procedure D. tR (HPLC) column A, gradient A = 2.58 min; MS (ESI): m/z =
389.3 [M+H]+, 265.3 [M-(2-chlorotoluene)+H]+, 125.1 [2-chlorotoluene+H]+;
[α]D25 = -10.0°(c = 1.5, CHCl3) ; 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.41 (m, 1H,
HCH),1.56-1.65 (m, 7H, HCH, 2CH2, 3-HCH, 4-CH), 1.76 (m, 1H, HCH), 1.85 (m,
1H, HCH), 1.93 (m, 1H, 3-HCH), 2.36 (s, 2H, 2NH), 2.74 (m, 1H, 2-CH), 3.42 (d, J =
13.4 Hz, 1H, 1-NHCH), 3.72 (d, J = 13.4 Hz, 1H, 1-NHCH), 3.77 (d, J = 14.0 Hz, 1H,
2-NHCH), 4.04 (d, J = 14.0 Hz, 1H, 2-NHCH), 7.14-7.19 (m, 3H, Ar-H), 7.22 (td, J =
7.4, 1.5 Hz, 1H, Ar-H), 7.28-7.31 (m, 2H, Ar-H), 7.36 (dd, J = 5.6 Hz and 3.5 Hz,
1H, Ar-H), 7.43 (dd, J = 7.4 Hz and 1.7 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3):
δ (ppm) = 24.8 (4-CH), 26.3, 26.7 and 29.7 (CH2), 35.1 (3-CH2), 43.0 (1-NCH2),
48.7 (2-NCH2), 53.4 (1-C), 54.9 (2-CH), 126.8, 127.0, 128.2, 128.5, 129.4, 129.6,
130.0 and 130.7 (Ar-CH), 133.6 and 134.1 (Ar-CCl), 137.9 and 138.3 (Ar-C);
HRMS (ESI-TOF) m/z [M+H]+ calcd. for C22H27N2Cl2 389.1551, found 389.1552.
(R)-N,N’-Bis(9-anthracenylmethyl)-1,2-diaminobicyclo[2.2.2]octane L12 was
obtained from 9-anthracenecarboxaldehyde as a yellow solid in 46% yield
according to the general procedure D. M.p. 171-173 °C ; tR (HPLC) column A,
25
gradient A = 3.14 min; MS (ESI): m/z =521.3 [M+H]+, [α]D = +152.6°(c = 1.2,
CHCl3) ; 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.63-1.68 (m, 2H, CH2), 1.78-1.85
(m, 6H, 2CH2, HCH, 4-CH), 1.91-1.96 (m, 1H, 3-HCH), 2.08-2.12 (m, 1H, HCH),
2.24 (m, 1H, 3-HCH), 2.98 (br d, 1H, 2-CH), 4.48 (d, J = 11.4 Hz, 1H, 1-NHCH),
4.53 (d, J = 11.4 Hz, 1H, 1-NHCH), 4.59 (d, J = 12.6 Hz, 1H, 2-NHCH), 4.91 (d, J =
12.6 Hz, 1H, 2-NHCH), 7.06-7.15 (m, 4H, Ar-H), 7.29-7.39 (m, 4H, Ar-H), 7.92 (d,
J = 8.4 Hz, 2H, Ar-H), 7.97 (d, J = 8.4 Hz, 2H, Ar-H), 8.08 (d, J = 8.9 Hz, 2H, Ar-H),
8.22 (d, J = 8.9, 2H, Ar-H), 8.35 (d, J = 7.3 Hz, 2H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 25.1 (4-CH), 25.4, 26.4, 26.5 and 30.0 (CH2), 35.9 (3-CH2), 37.9
(1-NCH2), 43.8 (2-NCH2), 53.8 (1-C), 58.7 (2-CH), 124.3, 125.0, 126.0, 126.1 and
127.0 (Ar-CH), 127.3 (Ar-C), 129.0 (Ar-CH), 130.2, 130.5, 131.6 and 131.7 (Ar-C);
HRMS (ESI-TOF) m/z [M+H]+ calcd. for C38H37N2 521.2957, found. 521.2950.
(R)-N,N’-Bis(2-methoxybenzyl)-1,2-diaminobicyclo[2.2.2]octane
L8
was
obtained from 2-methoxybenzaldehyde as colourless oil in 78% yield
a
according to the general procedure D. tR (HPLC) column A, gradient A = 2.16
min; MS (ESI): m/z
=
121.0 [2-methylmethoxyphenyl+H]+, 261 [M-(2-
methylmethoxyphenyl)+H]+, 381.3 [M+H]+; [α]D = -53.6°(c = 1.2, CHCl3); 1H
NMR (400 MHz, CDCl3): δ (ppm) = 1.59-2.12 (m, 11H, 5CH2, 4-CH), 2.81 (m, 1H,
2-CH), 3.39 (s, 3H, OCH3), 3.42 (d, J = 12.8 Hz, 1H, 1-NHCH), 3.61 (d, J = 12.8 Hz,
1H, 1-NHCH), 3.70 (s, 3H, OCH3), 3.79 (d, J = 13.4 Hz, 1H, 2-NHCH), 4.39 (d, J =
13.4 Hz, 1H, 2-NHCH), 6.68 (d, J = 8.3 Hz, 1H, Ar-H), 6.81(d, J = 8.3 Hz, 1H, Ar-H),
6.93 (t, J = 7.4 Hz, 2H, Ar-H), 7.18-7.34 (m, 4H, Ar-H); 13C NMR (100 MHz, CDCl3):
δ (ppm) = 24.4 (4-CH), 25.4, 25.7, 26.0, 28.8 and 32.4 (CH2), 40.9 and 46.4
(NCH2), 53.6 (1-C), 55.1 (OCH3), 55.2 (OCH3), 55.5 (2-CH), 110.2, 110.4, 120.8,
128.8 and 129.6 (Ar-CH), 129.8 (Ar-C), 131.1 (Ar-CH), 157.4 and 157.9 (Ar-
COCH3); HRMS (ESI-TOF) m/z [M+H]+ calcd. for C24H33N2O2 381.2542, found
381.2543.
25
General procedure E for the nitroaldol reaction (Henry reaction):
Ligand L10 (12 mol%, 0.018 mmol, 7.6 mg) and Cu(OAc)2 (10 mol%, 0.015
mmol, 2.1 mg) were dissolved in 2-propanol (0.5 mL) and stirred at room
temperature for 10 min. The deep blue reaction mixture was cooled to 0 °C and
aldehyde (1 equiv., 0.15 mmol) and nitromethane (10 equiv., 1.5 mmol, 80 µL)
were added. The reaction mixture was left stirring at 0 °C for 10 to 72 h.
Solvents were removed under reduced pressure and the residue was directly
purified on a silica gel column eluting with cyclohexane/EtOAc (8:1-4:1, v/v) to
yield the corresponding product.
(R)-N,N’-Bis(2-furanylmethyl)-1,2-diaminobicyclo[2.2.2]octane
L9
was
obtained from 2-furaldehyde as a light brown oil in 60% yield according to the
general procedure D. tR (HPLC) column A, gradient A = 1.80 min; MS (ESI): m/z =
Configuration assignment. The absolute configuration was assigned (S) for all
the nitroalcohol adducts by comparison with previously published retention
times in chiral HPLC.[4c,6a,6c,16]
25
221.2 [M-(2-methylfuran)+H]+, 301.0 [M+H]+; [α]D = -11.8°(c = 1.4, CHCl3); 1H
NMR (400 MHz, CD3CN): δ (ppm) = 1.29-1.35 (m, 1H, HCH), 1.37-1.41 (m, 1H, 3-
HCH), 1.49-1.71 (m, 8H, 3CH2, HCH, 4-CH), 1.83-1.89 (m, 1H, 3-HCH), 2.65 (m,
1H, 2-CH), 3.41 (d, J = 13.9 Hz, 1H, 1-NHCH), 3.58 (d, J = 13.9 Hz, 1H, 1-NHCH),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
A. Metsala, M. Lopp, T. Kanger, J. Org. Chem. 2010, 75, 1313-1316; g)
Y. Wei, L. Yao, B. Zhang, W. He, S. Zhang, Tetrahedron 2011, 67,
8552-8558; h) A. Chougnet, G. Zhang, K. Liu, D. Häussinger, A. Kägi, T.
Allmendinger, W.-D. Woggon, Adv. Synth. Catal. 2011, 353, 1797-
1806; i) G. Blay, V. Hernandez-Olmos J. R. Pedro, synlett 2011, 9,
1195-1211; j) Y. Q. Ji, Z. M. A. Judeh, Tetrahedron 2011, 67, 4086-
4092; k) Y. Q. Ji, G. Qi, Z. M. A. Judeh, Eur. J. Org. Chem. 2011, 4892-
4898; l) Y. Zhou, Y. Gong, Eur. J. Org. Chem. 2011, 6092-6099; m) Y.
Zhou, J. Dong, F. Zhang, Y. Gong, J. Org. Chem. 2011, 76, 588-600; n)
F. Liu, S. Gou, L. Li, P. Yana, C. Zhao, J. Mol. Catal. A: Chem. 2013,
379, 163-168 ; o) F. Liu, S. Gou, L. Li, Appl. Organometal. Chem. 2014,
28, 186-193 ; p) L. Filippova, Y. Stenstrøm, T. V. Hansen, Molecules
2015 20, 6224-6236 .
Acknowledgements
The authors thank the CNRS, the Université de Montpellier, the
Université de Lorraine for financial support. The CINES/CEA
CCRT/IDRIS is thanked for allocation of computing time (project
A0010807449).
Keywords: Asymmetric catalysis • nitroaldol reaction • bicyclic
1,2-diamine • copper • DFT calculations
[9]
P. Milbeo, L. Moulat, C. Didierjean, E. Aubert, J. Martinez, M. Calmès, J.
Org. Chem. 2017, 73, 3144-3151.
[10] For recent examples, see: a) C. André, B. Legrand, L. Moulat, E.
Wenger, C. Didierjean, E. Aubert, M.-C. Averlant-Petit, J. Martinez, M.
Amblard, M. Calmès, Chem. Eur. J. 2013, 19, 16963-16971 ; b) B.
Legrand, C. André, L. Moulat, E. Wenger, C. Didierjean, E. Aubert, M.
C. Averlant-Petit, J. Martinez, M. Calmès, M. Amblard, Angew. Chem.
Int. Ed. 2014, 53, 13131-13135 ; c) B. Legrand, C. André, L. Moulat, C.
Didierjean, P. Hermet, J. L. Bantignies, J. Martinez, M. Amblard, M.
Calmès, Chem. Eur. J. 2016, 22, 11986-11990.
[11] P. Milbeo, K. Maurent, L. Moulat, A. Lebrun, C. Didierjean, E. Aubert, J.
Martinez, M. Calmès, Tetrahedron 2016, 72, 1706-1715.
[12] Toluene complex of copper(I) triflate (R. G. Solomon, J. K. Kochi, J.C.S.
Chem. Comm. 1972, 559-560) has been previously used for in situ-
formation of efficient chiral copper catalysts of the asymmetric Henry
reaction; see for example references 6h.
[13] A. D. Becke, J. Chem. Phys. 1993, 98, 5648-5652.
[14] S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys. 2010,
132, 154104-154119.
[15] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev., 2005, 105, 2999-3093.
[16] M. Bandini, F. Piccinelli, S. Tommasi, A. Umani-Ronchi, C. Ventrici,
Chem. Commun. 2007, 616–618.
_____________
[1]
For examples of review, see: a) Y. L. Bennani, S. Hanessian, Chem.
Rev. 1997, 97, 3161-3195; b) D. Lucet, T. Le Gall, C. Mioskowski,
Angew. Chem. Int. Ed. 1998, 37, 2580-2627; c) J.-C. Kizirian, Chem.
Rev. 2008, 108, 140-205; d) O. O. Grygorenko, D. S. Radchenko, D. M.
Volochnyuk, A. A. Tolmachev, I. V. Komarov, Chem. Rev. 2011, 111,
5506-5568; e) B. Karimi, D. Enders, E. Jafari, Synthesis 2013, 2769-
2812; f) X. Liu, K. Zheng, X. Feng, Synthesis 2014, 2241-2257; g) D.
Lowiscki, S. Bas, J. Mlynarski, Tetrahedron 2015, 71, 1339-1394; h) H.
Yang, X. Yang, W. Tang, Tetrahedron 2016, 72, 6143-6174; i) S. Shaw,
J. D. White, Acc. Chem. Res. 2016, 49, 1825-1834; j) X. Chen, Z. Lu,
Org. Biomol. Chem. 2017, 15, 2280-2306; k) C. Hui, F, Pu, J. Xu, Chem.
Eur. J. 2017, 23, 4023-4036.
[2]
For selected examples, see: a) F. A. Luzzio, Tetrahedron, 2001, 57,
915-945; b) J. Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua,
Tetrahedron: Asymmetry 2006, 17, 3315-3326; c) C. Palomo, M.
Oiarbide, A. Laso, Eur. J. Org. Chem. 2007, 2561-2574; d) A. K.
Shiryaev, Curr. Org. Chem. 2012, 16, 1788-1807; e) N. Ananthi, S.
Velmathi, Indian J. Chem. 2013, 52B, 87-108; f) T. Arai, A. Joko, K.
Sato, Synlett 2015, 23, 209-2014; g) G. Novakova, P. Drabina, J.
Svoboda, M. Sedlak, Tetrahedron: Asymmetry 2017, 28, 791-796.
N. Ono, The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001.
For selected examples, see: a) B. M. Trost, V. S Yeh, H. Ito, N.
Bremeyer Org. Lett. 2002, 4, 2621-2623; b) A. Kamal, G. B. Ramesh
Khanna, T. Krishnaji, R. Ramu Bioorg. Med. Chem. Lett. 2005, 15, 613-
615; c) G. Blay, L. R. Domingo, V. Hernández-Olmos, J. R. Pedro,
Chem. Eur. J. 2008, 4725-4730; d) R. I. Kureshy, A. Das, N. H. Khan, S.
H. R. Abdi, H. C. Bajaj, ACS Catal. 2011, 1, 1529-1535.
[3]
[4]
[5]
[6]
H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J. Am. Chem. Soc.
1992, 114, 4418-4420.
For selected examples, see: a) D. A. Evans, D. Seidel, M. Rueping, H.
W. Lam, J. T. Shaw, C. W. Downey, J. Am. Chem. Soc. 2003, 125,
12692-12693; b) S. K. Ginotra, V. K. Singh, Org. Biomol. Chem. 2007,
5, 3932-3937; c) Y. Xion, F. Wang, X. Huang, Y. Wen, X. Feng, Chem.
Eur. J. 2007, 13, 829-833; d) R. Kowalczyk, L. Sidorowicz, J.
Skarzewski, Tetrahedron: Asymmetry 2008, 19, 2310 – 2315; e) N.
Sanjeevakumar, M. Periasamy, Tetrahedron: Asymmetry 2009, 19,
1842–1847; f) W. Jin, X. Li, Y. Huang, F. Wu, B. Wan, Chem. Eur. J.
2010, 16, 8259-8261; g) W. Jin, X. Li, B. Wan, J. Org. Chem. 2011, 76,
484-491; h) J. D. White, S. Shaw, Org. Lett. 2012, 14, 6270-6273; i) M.
Kannan, T. Punniyamurthy, Tetrahedron: Asymmetry 2014, 25, 1331-
1339; j) Z. Chunhong, F. Liu, S. Gou, Tetrahedron: Asymmetry 2014,
25, 278–283; k) S. V. Malhotra, H. C. Brown, RSC Adv., 2014, 4,
14264-14269; l) H. Mei, X. Xiao, X. Zhao, B. Fang, X. Liu, L. Lin, X.
Feng, J. Org. Chem. 2015, 2272-2280; m) H. Cruz, G. Aguirre, D.
Madrigal, D. Chávez, R. Somanathan, Tetrahedron: Asymmetry 2016,
27, 1217-1221.
[7]
[8]
For selected example, see: a) J. Park, K. Lang, K. A. Abboud, S. Hong,
J. Am. Chem. Soc. 2008, 130, 16484-16485; b) S. Handa, K. Nagawa,
Y. Sohtome, S. Matsunaga, M. Shibasaki, Angew. Chem. Int. Ed. 2008,
47, 3230-3233; c) R. Kowalczyk, P. Kwiatkowski, J. Skarzewski, J.
Jurczak, J. Org. Chem. 2009, 74, 753-756; d) K. Lang, J. Park, S. Hong,
Angew. Chem. Int. Ed. 2012, 51, 1620-1624; e) Y.-L. Wei, K.-F. Yang,
L. Li, Z.-J. Zheng, Z. Xua, L.-W. Xu, RSC Adv. 2014, 4, 37859-37867.
For selected examples, see: a) H. Maheswaran, K. L. Prasanth, G. G.
Krishna, K. Ravikumar, B. Sridharb, M. L. Kantam, Chem. Commun.,
2006, 4066-4068; b) T. Arai, M. Watanabe, A. Yanagisawa, Org. Lett.
2007, 18, 3595-3597; c) G. Blay, E. Climent, I. Fernandez, V.
Hernandez-Olmos, J. R. Pedro, Tetrahedron: Asymmetry 2007, 18,
1603-1612; d) T. Arai, R. Takashita, Y. Endo, M. Watanabe, A.
Yanagisawa, J. Org. Chem. 2008, 73, 4903-4906; e) G. Qi, Y. Q. Ji, Z.
M. A. Judeh, Tetrahedron 2010, 66, 4195-4205; f) A. Noole, K. Lippur,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701452
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Bicyclic diamine ligands
FULL PAPER
Pierre Milbeo, Laure Moulat, Claude
Didierjean, Emmanuel Aubert, Jean
Martinez, Monique Calmès*
Page No. – Page No.
C1-Symmetric 1,2-diamino
bicyclo[2.2.2]octane ligands in
Copper-catalyzed asymmetric Henry
Reaction: catalyst development and
DFT studies
The C1-symmetric (R)-N,N’-Bis(1-naphthylmethyl)-1,2-diaminobicyclo[2.2.2]octane
ligand with Cu(OAc)2 proved to be the most effective copper catalyst among those
tested for the asymmetric Henry reaction of nitromethane with various aldehydes.
DFT calculations of both the optimized copper complex conformations, and the
most stable transition states of the reaction supported the preferential formation of
S products in agreement with the experimental results.
This article is protected by copyright. All rights reserved.