Asymmetric Henry reaction catalyzed by chiral secondary diamine-copper(II) complexes

Article abstract of DOI:10.1016/j.tetasy.2008.09.032

The enantioselective Henry reaction was efficiently carried out under mild reaction conditions in 96% ethanol. The chiral C₂-symmetric, secondary bisamines based on the 1,2-diaminocyclohexane framework and copper(II) acetate were found to promo

Full text of DOI:10.1016/j.tetasy.2008.09.032

Tetrahedron: Asymmetry 19 (2008) 2310–2315
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric Henry reaction catalyzed by chiral secondary
diamine-copper(II) complexes
*
_
Rafał Kowalczyk, Łukasz Sidorowicz, Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective Henry reaction was efficiently carried out under mild reaction conditions in 96%
ethanol. The chiral C2-symmetric, secondary bisamines based on the 1,2-diaminocyclohexane framework
and copper(II) acetate were found to promote the asymmetric nitroaldol reaction. Aromatic and aliphatic
aldehydes were reacted with nitromethane to provide the corresponding b-nitroalcohols in very good
yields and enantioselectivities up to 94%.
Received 28 August 2008
Accepted 30 September 2008
Available online 22 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The asymmetric Henry (nitroaldol) reaction provides easy
access to chiral b-nitroalcohols. These products can be further con-
verted into valuable chiral building blocks, such as 1,2-aminoalco-
Thus, in order to correlate their catalytic activity and selectivity,
we obtained a set of ligands with heteroaromatic, ortho-, meta- and
para-substituted as well as with branched, aromatic moieties.
Various chiral diamines were prepared by a two-step synthesis
starting from easily available (1R,2R)-(+)-1,2-diaminocyclohexane
hols,
a-hydroxy acids, 1,2-diamines, and other precursors of
biologically active compounds.1 Due to the practical importance
of the reaction, much attention has been paid to its enantioselec-
tive derivatives. Both organocatalytic and metal-catalyzed proto-
cols have been developed so far.2 Chiral copper complexes have,
in particular, attracted much interest in this respect, and in some
cases afforded nitroaldols with impressive enantioselectivities.3
Both secondary3h,i,n and tertiary amines3c,j are amongst the suc-
cessfully applied ligands, providing b-nitroalcohols with ee’s up
to 99%. Despite significant advances in this field, there are some
shortcomings such as rather complex ligand structures, substrate
specificity limitations or the need for anhydrous reaction condi-
tions. All these obstruct the general use of the direct nitroaldol
reaction, and encourage further research.
L
-tartrate and the respective aldehydes with no need for purifica-
tion of the imine4 (Scheme 1). The corresponding tertiary diamine
1o was obtained from 1n via its N-methylation according to the
literature procedure.8
Next, ligands 1a–o were examined in the reaction of nitrometh-
ane with benzaldehyde in the presence of 12 mol % of chiral di-
amine and 10 mol % of Cu(OAc)2. We found that unlike in
Bandini’s3h protocol, moisture and air do not have to be avoided
in this reaction (see below). Thus, water containing ethanol (96%)
was generally used as a solvent under aerobic conditions at 0 °C.9
The results summarized in Table 1 show that these conditions
simultaneously gave good yield and enantiomeric excess for the
desired product (see Scheme 2).
The ligands with ortho-substituted aromatic moieties 1f–i, m,
and a 2,6-disubstituted one 1l gave products with up to 84% ee.
Among them, those with 2-chloro 1i and 2,6-dichloro 1l substitu-
ents afforded relatively better results, while the presence of elec-
tron-donating groups in 1f and 1h gave ee of only 66% and 67%,
respectively. Increasing the steric hindrance in 1g further did not
improve enantioselectivity.
Chiral secondary vic-diamines can be synthesized in a simple
way from the readily available precursors.4 They have turned out
to be effective ligands for many metal-catalyzed asymmetric
transformations.3h,l,n,5b,7 In spite of the increased acidity of the
N–H proton,6 they form stable metal complexes creating a chiral
environment for the catalytic reaction. The stereogenic centers
are located in the carbon skeleton, and after complexation at the
nitrogen atoms as well.7 The potential merits of this chiral frame-
work along with the recent results obtained by Bandini et al. for
ligands of this type with thienyl pedants3h encouraged us to eval-
uate more broadly simple C2-symmetric secondary diamines in the
asymmetric nitroaldol reaction.
The best results were obtained for ligands 1a, 1b, 1j, 1k, and 1n
with ee’s close to each other, regardless of the differences in size
and electronic character of their aromatic moieties. It is notable
that tertiary diamine 1o, in comparison to 1n, gave lower yields
and enantioselectivities.
Further experiments (Table 2) were carried out using 1k. Thus,
* Corresponding author. Tel.: +48 71 320 2464; fax: +48 71 328 4064.
_
under Bandini’s reaction conditions (23 °C in absolute ethanol)3h
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skarzewski).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.032

R. Kowalczyk et al. / Tetrahedron: Asymmetry 19 (2008) 2310–2315
2311
CHO
NH3 O2C
OH
OH
N
N
+
R
Ar
Ar
NH3
O2C
Ar:
furyl 1a
1-naphthyl 1b
2-naphthyl 1c
9-anthryl 1d
mesityl 1e
2-(MeO)C6H5 1f
CHO
NaBH4
O
2-(C8H17O)C6H5 1g
2-(HO)C6H5 1h
2-ClC6H5 1i
MeI/LiOH
CHO
1n
NH HN
1a-n
CH2Cl2-H2O
3-ClC6H5 1j
N
N
4-ClC6H5 1k
2,6-ClC6H4 1l
2-BrC6H5 1m
4-BrC6H5 1n
Ar
Ar
Ar
Ar
Me Me
1o
Scheme 1.
Table 1
Screening diamine ligands in the Henry reaction of benzaldehyde and nitromethanea
Table 2
Nitroaldol reaction of benzaldehyde and nitromethane catalyzed by 1k–Cu(OAc)2
a
Entry
Ligandb
Yieldc (%)
eed (%)
Entry
T (°C)
Yieldb (%)
eec (%)
1e
2e,f
3e,g,f
4g,f
5
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1e
1f
1g
1h
1i
1j
1k
1l
62
57
43
59
80
75
92
47
82
79
94
83
92
19
79
86
95
69
82
99
42
87
89
56
63
89
91
81
86
90
87
53
67
68
66
82
89
91
84
78
89
77
1d,e
2d
3
4
5
23
23
23
0
0
0
0
0
0
0
89 (NMR)
91
85
85
90
93
91
90
91
80
92
95
75
32
42
95
81
48
99
77
6f
6
7
8
9
7f
8g
9g,h
10g,i
10h
11
12
13
13
14
15
16
17
18
19
20
a
Reactions were performed on
a 0.5 mmol scale, 12 mol % of diamine 1k,
10 mol % of Cu(OAc)2ꢀnH2O, 10 equiv of CH3NO2 in ethanol (96%) for 48 h.
b
Yield of isolated product.
Enantiomeric excess determined by HPLC on a Chiracel OD-H column.
c
d
Bandini’s protocol was applied: dry EtOH, dried glassware under argon.
e
Conversion by 1H NMR after 80 min.
f
6 mol % of 1k and 5 mol % of Cu(OAc)2ꢀnH2O was used.
g
Complex 2 was used.
1m
1n
1o
h
10 mol % of DIPEA was used.
2 mol % of DIPEA was used.
i
a
Reactions were performed on a 0.5 mmol scale, 12 mol % of respective diamine
1a–1o, 10 mol % of Cu(OAc)2ꢀnH2O, 10 equiv of CH3NO2 in ethanol (96%) at 0 °C for
48 h.
to 0 °C caused the stereoselectivity to increase to 90% ee, although
with significant lowering of the yield after 16 h (entry 4). Running
this experiment for 48 h, 95% yield and 91% ee were obtained
(entry 6). After changing the molar ratio of ligand/copper from
1.2 to 2.4, the yield decreased to 42% without any changes in ee
(entry 5). Halving the amounts of both the ligand and copper salt
caused no change in the stereoselectivity (90%), but the yield was
lowered slightly (entry 7). Interestingly, in the presence of 1k,
but without a Cu-salt no nitroalcohol product was detected (unre-
acted aldehyde was recovered in 94%). This implies that the ligand
itself, as an amine, is not a suitable promoter for this reaction.10
To learn more about the nature of the catalyst, complex 1k–
Cu(OAc)2 2 was prepared and isolated in 61% yield upon single
crystallization from CH2Cl2/n-hexane. Its application to the nitro-
aldol reaction revealed that the desired product was obtained in
91% ee and 48% yield after 48 h at 0 °C (Table 2, entry 8). The yield
of the product increased up to 99% when 10 mol % of DIPEA was
added with some loss of ee (entry 9). When the reaction was per-
formed with only 2 mol % of DIPEA, the nitroalcohol was obtained
in 92% ee and 77% yield (entry 10).
b
Ligand structure according to Scheme 1.
Yield of isolated product.
Enantiomeric excess determined by HPLC using Chiracel OD-H column.
Evaporation under reduced pressure before purification of the product by
c
d
e
chromatography.
f
Reaction was performed in 2-propanol.
Reaction was performed at 23 °C.
Reaction was performed in nitromethane.
g
h
O
OH
Ligand 1a-o
NO2
+ CH3NO2
H
(S)
Cu(OAc)2·nH2O
EtOH, 0ºC
Scheme 2.
with this ligand, the product was obtained with 91% ee and 89%
conversion (1H NMR) after 80 min. The reaction performed under
these conditions for 16 h resulted in 95% yield and 85% ee (entry
2). The same enantioselectivity was observed for reaction in 96%
ethanol (entry 3) after 16 h. Decreasing the reaction temperature
The reaction catalyzed by (R,R)-1a–o copper complexes, as well
as by the Bandini3h system, led to the corresponding b-nitroalcohol
with an (S)-configuration at the stereogenic center. Having in mind

2312
R. Kowalczyk et al. / Tetrahedron: Asymmetry 19 (2008) 2310–2315
In order to examine the scope of the reaction, we applied ligand
Cl
1k (12 mol %) hydrated Cu(OAc)2 (10 mol %) in EtOH (96%) to the
nitroaldol reaction of various aldehydes (Table 3).
A variety of 2, 3 or 4-substituted aromatic, heteroaromatic, and
aliphatic aldehydes provided respective b-nitroalcohols with good
to high yields (up to 99%) and with enantioselectivities ranging
from 79% to 94%. It should be noted that the electronic character
of the substituent as well as its steric hindrance has rather slight
influence on the enantioselectivities. The ligands which were
effective in the nitroaldol reaction of benzaldehyde 1a, 1d, and
1k performed equally well with a branched substrate namely
p-biphenylcarbaldehyde (entries 2–4). Aldehydes with electron-
withdrawing substituents led to products with higher yields, and
this result correlates with the increased electrophilicity of the
substrate.
Encouraged by the efficiency of the 1k–Cu(OAc)2 catalytic sys-
tem, we also performed the reaction between benzaldehyde and
nitroethane. Unfortunately, the corresponding diastereoisomeric
products were obtained in low ee (major 27%, minor 30%) and poor
total yield (19%).
(R)
O
NH
OH
H
H
N
O
NO2
(R)
H
(S)
OAc
N
Cu
Ph
O
H
R, R, RN, RN
Cl
Figure 1. Transition state model explaining the observed stereochemical outcome.
both possible complexes with the different absolute configurations
at the nitrogen atoms,7 a plausible mechanism can be represented
by the transition state model shown in Figure 1.
According to the previously reported considerations,3a,b we
assume the coordination mode where the carbonyl oxygen atom
is coordinated at one of the equatorial positions, and the oxygen
atom of nitromethane approaches the metal center from the axial
side. This positioning of the reactants seems the most favorable
orientation taking into account steric and electronic consider-
ations, and ensures activation of both electrophile and nucleophile.
Thus, after deprotonation by an acetate anion3b or by the other
external base, the resulting nitronate ion approaches the aldehyde
from the Re face (Fig. 1) to give the observed (S)-product. Other
possibilities seem to be restricted by the unfavorable steric interac-
tions between the phenyl group of the aldehyde and aromatic moi-
ety of the ligand.
3. Conclusion
In conclusion, we have presented the application of simple
chiral secondary diamines obtained from 1,2-diaminocyclohexane
to the asymmetric nitroaldol reaction. The product formation
required 12 mol % of ligand and 10 mol % of Cu(OAc)2 hydrate
under mild conditions in 96% aq ethanol. Commercial grade
solvent and reagents were applied without any precautions to
provide products with good to excellent yields and enantioselec-
tivities up to 94%. The reaction stereochemical outcome was in
agreement with the generally accepted transition state model.
Based on this reasoning and the X-ray structure of Bandini’s
complex,3h we can assume that stereoselectivity in this reaction
results from the configuration on the nitrogen and distribution of
the possible diastereomeric complexes. The conformation of the
resulting diamine-copper species (R,R,RN,RN), where the largest
substituents on nitrogen are parallel to each other and oriented
in opposite directions, is then similar to those observed for effec-
tive copper–BOX complexes.3a,b
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were measured on a Bruker
Avance DRX (1H, 300 MHz) spectrometer using TMS as an internal
standard. Observed rotations at 589 nm were measured using an
Optical Activity Ltd. Model AA-5 automatic polarimeter. High-res-
olution mass spectra (HRMS) were recorded on a Mariner PE Bio-
systems unit using the ESI technique. The enantiomeric
composition of nitroaldols was determined by HPLC analysis using
a chiral stationary phase (Chiracel OD-H or Daicel Chiralpak AD-H).
The absolute configuration of the major enantiomer was assigned
according to the sign of the specific rotation as well as of the reten-
tion time with the reported data.3b,i
Separations of products by chromatography were performed on
Silica Gel 60 (230–400 mesh) purchased from Fluka. Thin layer
chromatography analyses were performed using Silica Gel 60 per-
colated plates (Fluka). Ethanol was dried by heating with CaH2 fol-
lowed by distillation prior to use. For the general applications,
ethanol 96% (aq) was used without any precautions. Liquid alde-
hydes were freshly distilled before use.
Table 3
Nitroaldol reaction of aldehydes (RCHO) and nitromethane catalyzed by 1k–
a
Cu(OAc)2
Entry
R
Yieldb (%)
eec (%)
1
2
Ph
95
87
91
83
94
99
76
89
91
79
90
77
65
64
67
91
83
83
89
83
82
81
80
86
83
87
94
85
79
92
p-PhC6H4
p-PhC6H4
p-PhC6H4
p-ClC6H4
p-O2NC6H4
p-MeC6H4
2-Naphthyl
1-Naphthyl
o-MeOC6H4
m-ClC6H4
PhCH@CH–
c-C6H12
3d
4e
5
6
7
8
9
10
11
12
13
14
15
4.2. Ligands
2-Furyl
t-Bu
Diamines 1a,7b 1b,7b,11 1d,12 1e,11,13 1f,14 1h,15 and 1n12 are
known compounds. For other ligands, procedures are presented
below.
a
Reactions were performed on a 0.5 mmol scale, 12 mol % of ligand 1k, 10 mol %
of Cu(OAc)2ꢀnH2O, 10 equiv of CH3NO2 in ethanol (96%) at 0 °C for 48 h.
b
Yield of isolated product.
Enantiomeric excess determined by HPLC on Chiracel OD-H or Chiralpak AD-H
c
4.2.1. General procedure4b for ligands 1c, 1i, 1j, 1k, 1m
Potassium bicarbonate (anhydrous, 2.0 equiv) was added to vig-
orously stirred suspension of (1R,2R)-(+)-1,2-diaminocyclohexane
columns.
d
Ligand 1d was applied.
Ligand 1a was applied.
e

R. Kowalczyk et al. / Tetrahedron: Asymmetry 19 (2008) 2310–2315
2313
(ESI, [M+H]+) calcd for [C36H58N2O2+H]+ 551.4571; found
551.4579.
L
-tartrate salt (1.0 equiv) in water (46 mL/10 mmol of salt) at rt.
Then ethanol (96%, 20 mL/10 mmol of salt) was added, followed
by solution of an aldehyde (2.0 equiv) and CH3SO3H (0.1 mL) in
dichloromethane. The biphasic mixture was stirred at rt overnight,
refluxed for 2 h, and concentrated in vacuo to evaporate organic
solvents. After cooling, ethyl acetate was added (50 mL), the phases
were separated, and the water layer was washed with AcOEt
(3 ꢁ 50 mL). Combined organic layers were dried over Na2SO4
and solvent was evaporated in vacuo giving a crude diimine, which
was directly used in the next step.
The diimine was dissolved in MeOH (5 mL/10 mmol). In the
case of non-soluble compounds, toluene was added to dissolution.
The resulting mixture was cooled on an ice-bath, and NaBH4
(2.5 equiv) was added in one portion. Stirring at this temperature
was maintained until gas evaporation was stopped, and then the
mixture was allowed to reach rt and then refluxed for 2 h. The sol-
vents were removed in vacuo and the residue was treated with
water (50 mL/10 mmol of salt) and dichloromethane (50 mL/
10 mmol of salt). Phases were separated, and the upper layer was
washed with CH2Cl2. The combined organic fractions were dried
over K2CO3, and the solvent was evaporated in vacuo. The product
was purified by column chromatography on silica gel (50 g/
10 mmol of salt, gradient CHCl3 to CHCl3/MeOH, 10:1, v/v) giving
the desired product.
4.2.4. Compound 1i
Ligand 1i was prepared according to the general procedure
starting from (1R,2R)-(+)-1,2-diaminocyclohexane L-tartrate salt
(1.52 g, 5.75 mmol). Part of the imine (536 mg, 1.49 mmol) was
reduced to afford 511 mg (93% yield after two stages) of the
desired product as a light yellow oil, Rf = 0.40 (CHCl3/EtOH, 20:1,
v/v), ½a D
ꢂ
¼ ꢃ62:0 (c 0.5, MeOH); IR (film): mmax 3296, 3065, 2928,
2855, 1572, 1445, 1126, 1038, 1049, 751 cmꢃ1
;
1H NMR d 7.39
(dd, J = 7.2 Hz, 2.0 Hz, 2H, ArH), 7.30 (dd, J = 7.2, 2.0 Hz, 2H, ArH),
7.12–7.22 (m, 4H, ArH), 3.95 (d, J = 13.8 Hz, 2H, CHAHB), 3.74 (d,
J = 13.8 Hz, 2H, CHAHB), 2.23–2.27 (m, 2H, 2 ꢁ CHN), 2.16 (br d,
J = 13.2 Hz, 2H, CH2), 2.02 (br s, 2H, 2 ꢁ NH), 1.70–1.73 (m, 2H,
CH2), 1.19–1.26 (m, 2H, CH2), 1.03–1.10 (m, 2H, CH2). 13C NMR d
138.5 (CAr IV°), 133.8 (CAr IV°), 130.0 (CAr), 129.4 (CAr), 128.1
(CAr), 126.8 (CAr), 61.1 (CHN), 48.4 (CHAHB), 31.7 (CH2), 25.1
+
(CH2). HRMS (ESI, [M+H]+) calcd for [C20H24N2Cl2+H] 363.1389;
found 363.1374.
4.2.5. Compound 1j
Ligand 1j was prepared according to the general procedure
starting from (1R,2R)-(+)-1,2-diaminocyclohexane L-tartrate salt
(1.32 g, 5.0 mmol). Part of the imine (500 mg, 1.39 mmol) was
reduced to afford 494 mg (92% yield) of the desired product as a
light yellow solid, mp = 53–55 °C; Rf = 0.36 (CHCl3/EtOH, 20:1,
4.2.2. Compound 1c
Ligand 1c was prepared according to the general procedure
starting from (1R,2R)-(+)-1,2-diaminocyclohexane L-tartrate salt
(500 mg, 1.9 mmol). The crude imine (628 mg) was reduced to
afford 399 mg (54% yield after two stages) of the desired product
as a light yellow solid, mp = 74–76 °C; Rf = 0.31 (CHCl3/EtOH,
v/v), ½a D
ꢂ
¼ ꢃ53 (c 0.5, MeOH); IR (film): mmax 3301, 3062, 2928,
2855, 1597, 1575, 1458, 1200, 1117, 868, 778, 683 cmꢃ1
;
1H
NMR d 7.30 (s, 2H, ArH), 7.16–7.25 (m, 6H, ArH), 3.85 (d,
J = 13.5 Hz, 2H, CHAHB), 3.61 (d, J = 13.5 Hz, 2H, CHAHB), 2.20–2.23
(m, 2H, 2 ꢁ CHN), 2.09–2.14 (m, 2H, CH2), 1.85 (br s, 2H, 2 ꢁ NH),
1.69–1.73 (m, 2H, CH2), 1.18–1.24 (m, 2H, CH2), 0.99–1.06 (m,
2H, CH2); 13C NMR d 143.3 (CAr IV°), 134.2 (CAr IV°), 129.7 (CAr),
128.1 (CAr), 127.0 (CAr), 126.2 (CAr), 61.0 (CHN), 50.4 (CHAHB),
31.7 (CH2), 25.1 (CH2). HRMS (ESI, [M+H]+) calcd for
[C20H24N2Cl2+H]+ 363.1389; found 363.1389.
20:1, v/v), ½a D
ꢂ
¼ þ15:9 (c 0.4, MeOH); IR (film): mmax 3297, 3051,
2925, 2856, 1599, 1508, 1450, 1126, 855, 813, 744, 473 cmꢃ1
;
1H
NMR d 7.74–7.83 (m, 8H, ArH), 7.41–7.49 (m, 6H, ArH), 4.08 (d,
J = 13.2 Hz, 2H, CHAHB), 3.83 (d, J = 13.2 Hz, 2H, CHAHB), 2.32–
2.35 (m, 2H, 2 ꢁ CHN), 2.21 (br d, J = 11.4 Hz, 2H, CH2), 2.02 (s,
2H, 2 ꢁ NH), 1.73–1.76 (m, 2H, CH2), 1.22–1.28 (m, 2H, CH2),
1.06–1.09 (m, 2H, CH2). 13C NMR d 139.0 (CAr IV°), 133.8 (CAr IV°),
132.9 (CAr IV°), 128.2 (CAr), 128.0 (CAr), 127.9 (CAr), 127.0 (CAr),
126.5 (CAr), 126.2(CAr), 125.7 (CAr), 61.2 (CHN), 51.2 (CHAHB), 31.9
(CH2), 25.4 (CH2). HRMS (ESI, [M+H]+) calcd for [C28H30N2+H]+
395.2482; found 395.2466.
4.2.6. Compound 1k
Ligand 1k was prepared according to the general procedure
starting from (1R,2R)-(+)-1,2-diaminocyclohexane L-tartrate salt
(778 mg, 2.95 mmol). Imine (1.014 g, 2.82 mmol) was reduced
affording 884 mg (83% after two stages) of the desired product as
4.2.3. Compound 1g
a light yellow oil, Rf = 0.32 (CHCl3/EtOH, 20:1, v/v), ½a D
(c 0.5, MeOH); IR (film): mmax 3299, 3027, 2928, 2854, 1597,
1490, 1457, 1091, 1015, 800 cmꢃ1 1H NMR d 7.22 (AB system,
ꢂ ¼ ꢃ46:2
(1R,2R)-Diaminocyclohexane (71 mg, 0.62 mmol, 1.0 equiv) in
toluene (2.0 mL) was added to the solution of the aldehyde
(293 mg, 1.25 mmol, 2.0 equiv) in toluene (4.0 mL), followed by
anhydrous MgSO4 (3.0 g). The resulting solution was stirred vigor-
ously for 24 h at rt, heated at reflux for 1 h, and then cooled. The
solid was filtered, and washed with toluene (2 ꢁ 10 mL). The fil-
trate was concentrated in vacuo, dried under high vacuum giving
320 mg of crude oily imine. The reduction was performed follow-
ing the general procedure affording 190 mg (55% yield after two
;
J = 14.6, 8.6 Hz, 8H, ArH), 3.83 (d, J = 13.3 Hz, 2H, CHAHB), 3.59 (d,
J = 13.3 Hz, 2H, CHAHB), 2.18–2.21 (m, 2H, 2 ꢁ CHN), 2.11 (br d,
J = 13.2 Hz, 2H, CH2), 1.84 (s, 2H, 2 ꢁ NH), 1.69–1.71 (m, 2H, CH2),
1.16–1.23 (m, 2H, CH2), 0.98–1.01 (m, 2H, CH2); 13C NMR d 139.7
(CAr IV°), 132.5 (CAr IV°), 129.4 (CAr), 128.5 (CAr), 60.9 (CHN), 50.2
(CHAHB), 31.6 (CH2), 25.1 (CH2). HRMS (ESI, [M+H]+) calcd for
[C20H24N2Cl2+H]+ 363.1389; found 363.1371.
stages) of
¼ ꢃ33:0 (c 0.2, MeOH); IR (film): mmax 3312, 2927, 2855,
1601, 1493, 1455, 1242, 1106, 751 cmꢃ1 1H NMR d 7.22 (dd,
a colorless oil; Rf = 0.72 (CHCl3/EtOH, 20:1, v/v),
½aꢂD
4.2.7. Compound 1l
;
Diamine 1l was prepared by the reduction of the corresponding
diimine.16
J = 7.2, 1.5 Hz, 2H, ArH), 7.16 (dt, J = 7.9, 1.5 Hz, 2H, ArH), 6.85
(t, J = 7.2 Hz, 2H, ArH), 6.77 (d, J = 7.9 Hz, 2H, ArH), 3.83–3.93
(m, 6H, 2 ꢁ CH2O + CHAHB), 3.61 (d, J = 13.2 Hz, 2H, CHAHB), 2.50
(br s, 2H, 2 ꢁ NH), 2.21–2.24 (m, 2H, 2 ꢁ CHN), 2.13 (br d,
J = 12.6 Hz, 2H, CH2), 1.65–1.70 (m, 6H, 3 ꢁ CH2), 1.18–1.37 (m,
22H, 11 ꢁ CH2), 1.03–1.06 (m, 2H, CH2), 0.87 (t, J = 6.6 Hz, 6H,
2 ꢁ CH3); 13C NMR d 157.1 (CAr IV°), 129.7 (CAr), 129.0 (CAr IV°),
127.9 (CAr), 120.1 (CAr), 110.9 (CAr), 67.9 (CH2O), 60.7 (CHN),
46.1 (CHAHB), 31.9 (CH2), 31.4 (CH2), 29.44 (CH2), 29.37 (CH2),
29.36 (CH2), 26.2 (CH2), 25.1 (CH2), 22.7 (CH2), 14.2 (CH3). HRMS
The diimine (428 mg, 1.0 mmol, 1.0 equiv) was suspended in
MeOH (5.0 mL) after which NaBH4 (190 mg, 5.0 mmol, 5.0 equiv)
was added portionwise for 10 min at rt, which caused gas libera-
tion. After 24 h, water was added (10 mL), the resulting mixture
was stirred for 5 min and the solvents were evaporated in vacuo.
The residue was treated with CH2Cl2 (10 mL) and brine (10 mL),
phases were separated and water layer was washed with CH2Cl2
(5 ꢁ 5 mL). Combined organic fractions were dried (K2CO3), and
solvent was evaporated giving 379 mg (88% yield) of white

2314
R. Kowalczyk et al. / Tetrahedron: Asymmetry 19 (2008) 2310–2315
crystals. Analytical sample was obtained by crystallization from
CH2Cl2/n-hexane, mp = 156–157 °C; ½a D ¼ ꢃ36:2 (c 0.9, EtOH); IR
(KBr): mmax 3280, 2919, 2851, 1561, 1471, 1436, 1114, 1087, 849,
776, 762 cmꢃ1 1H NMR d 7.24 (d, J = 7.8 Hz, 4H, ArH), 7.08 (t,
J = 7.8 Hz, 2H, ArH), 4.11 (d, J = 12.3 Hz, 2H, CHAHB), 3.90 (d,
J = 12.3 Hz, 2H, CHAHB), 2.26 (br d, J = 12.9 Hz, 2H, CH2), 2.16–
2.19 (m, 2H, 2 ꢁ CHN), 2.04 (br s, 2H, 2 ꢁ NH), 1.72–1.75 (m, 2H,
CH2), 1.18–1.32 (m, 2H, CH2), 0.97–1.10 (m, 2H, CH2); 13C NMR d
136.6 (CAr IV°), 136.1 (CAr IV°), 128.6 (CAr), 128.2 (CAr), 61.2
(CHN), 46.1 (CHAHB), 32.1 (CH2), 25.2 (CH2). HRMS (ESI, [M+H]+)
calcd for [C20H22N2Cl4+H]+ 431.0610; found 431.0620.
crude complex was dissolved in hot CH2Cl2 and treated with n-hex-
ane. Crystals are formed after 2 h of standing at rt. Resulting solid
was filtered, washed with n-hexane, and dried giving 358 mg
ꢂ
;
(61%) of blue crystals; ½aꢂD ¼ þ475 (c 0.016, CH2Cl2); IR (KBr): mmax
3220, 3176, 2935, 2860, 1616, 1583, 1493, 1393, 1332, 1094, 805,
668, 615, 494, 483, 325, 301 cmꢃ1; Anal. Calcd for C24H30Cl2Cu-
N2O4ꢀ0.5H2O: C 51.29; H 5.56; N 4.98. Found C 51.09; H 5.35; N 4.98.
4.3. General procedure for catalytic Henry reaction
Ligand (0.06 mmol, 12 mol %) and Cu(OAc)2ꢀnH2O (10.0 mg,
0.05 mmol, 10 mol %) were treated with ethanol (96% aq, 1.0 mL),
and the resulted deep blue to green solution was stirred for 1.0 h
at 23 °C without any other precautions. Then a solution of respec-
tive aldehyde (0.5 mmol, 1.0 equiv) in ethanol (0.5 mL) was added,
the reaction mixture was cooled to 0 °C (ice-water bath), stirred for
4.2.8. Compound 1m
Ligand 1m was prepared according to the general procedure
starting from (1R,2R)-(+)-1,2-diaminocyclohexane L-tartrate salt
(673 mg, 2.5 mmol). Part of the imine (355 mg, 0.74 mmol) was
reduced to afford 346 mg (85% yield afer two stages) of the desired
product as a light yellow oil, Rf = 0.57 (CHCl3/EtOH, 20:1, v/v),
15 min. followed by addition of CH3NO2 (270 lL, 5.0 mmol,
10 equiv) via syringe. After 48 h, the cold reaction mixture was
put into a plug of silica gel (30g, n-hexane/AcOEt 6:1,v/v) and affor-
ded the desired b-nitroalcohol. Products were analyzed by 1H NMR
(CDCl3), and measurement of specific rotations in CH2Cl2 or CHCl3
was determined. Enantiomeric excess was determined using HPLC
on Chiracel OD-H or Chiralpak AD-H chiral columns (flow rate:
1.0 mL/min, k = 225 nm). Reported values are listed below:
(S)-(+)-1-Phenyl-2-nitroethane-1-ol: Chiracel OD-H, n-hexane/
i-PrOH, 9:1, tminor = 13.8 min, tmajor = 16.6 min.
(S)-(+)-1-(4-Chlorophenyl)-2-nitroethane-1-ol: Chiracel OD-H,
n-hexane/i-PrOH, 9:1, tminor = 13.9 min, tmajor = 17.3 min.
(S)-(+)-1-Cyclohexyl-2-nitroethane-1-ol: Diacel Chiralpak AD-
H, n-hexane/i-PrOH, 9:1, tminor = 8.8 min, tmajor = 9.4 min.
(S)-(+)-1-(2-Methoxyphenyl)-2-nitroethane-1-ol: Chiracel OD-
H, n-hexane/i-PrOH, 9:1, tminor = 11.3 min, tmajor = 13.3 min.
(S)-(+)-1-(4-Nitrophenyl)-2-nitroethane-1-ol: Chiracel OD-H,
n-hexane/i-PrOH, 4:1, tminor = 12.0 min, tmajor = 14.4 min.
(+)-1-(2-Naphthyl)-2-nitroethane-1-ol: Chiracel OD-H, n-hex-
ane/i-PrOH, 4:1, tminor = 20.3 min, tmajor = 27.6 min.
(+)-1-(1-Naphthyl)-2-nitroethane-1-ol: Chiracel OD-H, n-hex-
ane/i-PrOH, 4:1, tminor = 9.7 min, tmajor = 14.4 min.
(S)-(+)-1-Nitro-4-phenyl-3-buten-2-ol: Chiracel OD-H, n-hex-
ane/i-PrOH, 4:2, tmajor = 17.5 min, tminor = 19.8 min.
(+)-1-(2-Furanyl)-2-nitroethane-1-ol: Chiralpak AD-H, n-hex-
ane-iPrOH, 95:5, tminor = 21.9 min, tmajor = 23.1 min.
(S)-(+)-1-tert-Butyl-2-nitroethane-1-ol: Chiralcel OD-H, n-hex-
ane-iPrOH, 95:5, tminor = 16.7 min, tmajor = 18.8 min.
½
a D
ꢂ
¼ ꢃ43:9 (c 0.5, MeOH); IR (film): mmax 3294, 3061, 2928,
2854, 2567, 1440, 1123, 1109, 1025, 749 cmꢃ1 1H NMR d 7.49
;
(d, J = 7.9 Hz, 2H, ArH), 7.40 (d, J = 7.2 Hz, 2H, ArH), 7.23 (t,
J = 7.2 Hz, 2H, ArH), 7.07 (dt, J = 7.9, 1.2 Hz, 2H, ArH), 3.94 (d,
J = 13.8 Hz, 2H, CHAHB), 3.73 (d, J = 13.8 Hz, 2H, CHAHB), 2.25–
2.28 (m, 2H, 2 ꢁ CHN), 2.17 (br d, J = 12.9 Hz, 2H, CH2), 2.09 (s,
2H, 2 ꢁ NH), 1.71–1.73 (m, 2H, CH2), 1.90–1.27 (m, 2H, CH2),
1.03–1.11 (m, 2H, CH2); 13C NMR d 140.0 (CAr IV°), 132.7 (CAr),
130.2 (CAr), 128.4 (CAr), 127.4 (CAr), 124.1 (CAr IV°), 61.1 (CHN),
50.9 (CHAHB), 31.7 (CH2), 25.1 (CH2). HRMS (ESI, [M+H]+) calcd
for [C20H24N2Br2+H]+ 451.0379; found 451.0395.
4.2.9. Compound 1o
Ligand 1o was prepared from diamine 1n according to the liter-
ature procedure.8
Iodomethane (120 mg, 0.8 mmol, 2.0 equiv) was added to solu-
tion of 1n (193 mg, 0.4 mmol, 1.0 equiv) in dichloromethane
(2.0 mL), and the resulting mixture was stirred for 4 h at rt. The
first portion of LiOHꢀH2O (17 mg, 1.0 equiv) was added that
resulted in clouding of the reaction mixture. The second portion
of LiOHꢀH2O (17 mg, 1.0 equiv) was added, stirring was continued
for 16 h and water (10 mL) was added. Phases were separated,
water layer was washed with CH2Cl2 (3 ꢁ 5 mL) and combined
organic fractions were dried (K2CO3). Solvent was evaporated
giving 201 mg of colorless oil. The product was purified by column
chromatography on silica gel (20 g, CHCl3/EtOH, 10:1, v/v) afford-
ing the desired product 106 mg (53%) as a light yellow oil;
(S)-(+)-1-(3-Chlorophenyl)-2-nitroethane-1-ol: OD-H, n-hex-
ane/i-PrOH, 9:1, tminor = 14.0 min, tmajor = 17.9 min.
(S)-(+)-1-(4-Phenylphenyl)-2-nitroethanol: OD-H, n-hexane/i-
PrOH, 9:1, tminor = 11.3 min, tmajor = 13.0 min.
Rf = 0.16 (CHCl3/EtOH, 20:1, v/v), ½a D
(film): mmax 3041, 3022, 2930, 2855, 2788, 1699, 1669, 1599,
1486, 1449, 1402, 1068, 1011, 833, 816, 798, 478 cmꢃ1 1H NMR
ꢂ ¼ þ10:9 (c 1.64, CH2Cl2); IR
;
d 7.38 (d, J = 8.1 Hz, 4H, ArH), 7.22–7.24 (m, 4H, ArH), 3.65–3.70
(m, 2H, CHAHB), 3.52 (d, J = 13.2 Hz, 2H, CHAHB), 2.56–2.59 (m,
2H, 2 ꢁ CHN), 2.17 (s, 6H, 2 ꢁ CH3), 1.90 (br d, J = 12 Hz, 2H, CH2),
1.72–1.75 (m, 2H, CH2), 1.10–1.24 (m, 4H, 2 ꢁ CH2); 13C NMR d
139.9 (CAr IV°), 131.2 (CAr), 130.6 (CAr), 120.4 (CAr IV°), 63.8
(CHN), 57.8 (CHAHB), 36.3 (CH3), 25.8 (CH2), 25.5 (CH2). HRMS
(ESI, [M+H]+) calcd for [C22H28N2Br2+H]+ 479.0692; found
479.0690.
Acknowledgment
We are grateful to the Ministry of Science and Higher Education
for financial support (Grant PBZ-KBN-126/T09/2004).
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