Enantioselective catalysts for the Henry reaction: Fine-tuning the catalytic components

Article abstract of DOI:10.1039/b9nj00243j

Catalysts for the asymmetric Henry reaction involving 1,6-bis(3-ethoxy-2- hydroxyphenyl)-(3S,4S)-(-)-diphenyl-2,5-diazahexane (H₂2) and copper salts have been investigated. Conditions for the conversion of 4-nitrobenzaldehyde to 2-nitro-1-(4-ni

Full text of DOI:10.1039/b9nj00243j

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Enantioselective catalysts for the Henry reaction: fine-tuning
the catalytic componentsw
Edwin C. Constable,* Guoqi Zhang, Catherine E. Housecroft,* Markus Neuburger,
Silvia Schaffner, Wolf-D. Woggon and Jennifer A. Zampese
Received (in Montpellier, France) 8th June 2009, Accepted 25th June 2009
First published as an Advance Article on the web 17th August 2009
DOI: 10.1039/b9NJ00243j
Catalysts for the asymmetric Henry reaction involving 1,6-bis(3-ethoxy-2-hydroxyphenyl)-(3S,4S)-
(ꢀ)-diphenyl-2,5-diazahexane (H22) and copper salts have been investigated. Conditions for the
conversion of 4-nitrobenzaldehyde to 2-nitro-1-(4-nitrophenyl)ethanol by reaction with nitromethane
have been optimized (5 mol% H22, 10 mol% CuI, THF, 295 K and 2 hours or 273 K and 12 hours)
resulting in 99% yield and 90–92% ee. These catalytic conditions are effective for other aromatic
aldehydes containing electron-withdrawing substituents, and for pyridine carbaldehydes;
representative aliphatic aldehydes were converted to the respective b-hydroxynitro derivatives with
good enantioselectivities, and in moderate yields. These catalytic conditions were found to be
ineffective for simple aromatic aldehydes or those containing electron-releasing substituents.
Introduction
In synthetic chemistry, the Henry (or nitroaldol) reaction is
becoming an increasingly important carbon–carbon bond
forming reaction,1–3 and the b-hydroxynitro compounds so
formed find application in the synthesis of key intermediates
such as chiral b-amino alcohols and a-hydroxyl carboxylic
acids.3–6 Current interest in enantioselective and diastereo-
selective Henry reactions7–13 has led to the development
of chiral catalysts containing copper,10,14–37 cobalt,38,39
chromium40–42 and zinc,43 as well as heterodimetallic
complexes.11,44 Schiff base ligands are central to many of these
Scheme 1 Structures of ligands and labeling for NMR spectroscopic
catalysts, the preparation of these compounds from amine and
carbonyl precursors being facile. In developing new catalysts
for the asymmetric Henry reaction, it is advantageous
for catalysis to be carried out under mild (ideally ambient)
reaction conditions. We have recently described catalytic
studies of the asymmetric Henry reaction using copper(II)
complexes of the chiral Schiff bases 1,6-bis(2-hydroxyphenyl)-
(3R,4R)-(ꢀ)-cyclohexane-1,2-diyl-2,5-diazahexa-1,5-diene,
1,6-bis(3-ethoxy-2-hydroxyphenyl)-(3R,4R)-(ꢀ)-cyclohexane-
1,2-diyl-2,5-diazahexa-1,5-diene and the reduced analogue of
the latter, H21 (Scheme 1).34 Of these, the most promising
catalyst was [Cu(1)] which produced moderate to high yields
and enantioselectivities which were optimal when reactions
were carried out in toluene rather than a polar solvent. We
observed that both the yield and the enantioselectivity were
enhanced when a second equivalent of Cu(OAc)2 was added to
the catalyst. We report here a detailed study of the use of
copper complexes of the reduced Schiff base ligand
assignment of H22.
Scheme 2 Catalytic asymmetric Henry reaction of 4-nitrobenzaldehyde
and nitromethane.
1,6-bis(ethoxy-2-hydroxyphenyl)-(3S,4S)-(ꢀ)-diphenyl-2,5-
diazahexane (H22, Scheme 2) as catalysts in the asymmetric
Henry reaction, including an assessment of the scope of
the most effective catalyst tested which uses H22 with two
equivalents of CuI, and gives both excellent yield and
enantioselectivity.
Department of Chemistry, University of Basel, Spitalstrasse 51,
CH 4056 Basel, Switzerland. E-mail: catherine.housecroft@unibas.ch;
Fax: +41 61 267 1018; Tel: +41 61 267 1008
w Electronic supplementary information (ESI) available: CD spectrum
of ligand H22. CCDC reference numbers 739378–739380. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b9NJ00243j
Experimental
General
Commercially available chemicals were of reagent grade and
1
used without further purification. H and 13C NMR spectra
ꢁc
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were recorded on Bruker DRX-500 or DPX-400 MHz
1
[Cu(2)]
spectrometers; chemical shifts for H and 13C NMR spectra
A solution of Cu(OAc)2 (18.1 mg, 0.100 mmol) in MeOH
(5 cm3) was added to a solution of H22 (51.2 mg, 0.100 mmol)
in MeOH (5 cm3) at room temperature. A pale green suspension
formed upon stirring the reaction mixture for 30 min. The
product was separated by filtration and was washed with
MeOH (5 cm3). After drying in vacuo, [Cu(2)] was isolated
as a green solid (47.0 mg, 82%). IR (solid, cmꢀ1) 3200m,
2970w, 1589m, 1473s, 1452s, 1444s, 1321w, 1284m, 1231s,
1086m, 1036m, 1013m, 978m, 965m, 937w, 877w, 851s,
770m, 745s, 701s; ESI-MS (MeOH) m/z 596.1 [M + Na]+
(base peak, calc. 596.2). Found C 65.85, H 5.94, N 4.56%;
C32H34CuN2O4ꢃ0.6MeOH requires C 65.98, H 6.18, N 4.72%.
are referenced to residual solvent peaks with respect to
TMS = d 0 ppm. Infrared spectra were recorded on a
Shimadzu FTIR-8400S spectrophotometer with solid
samples on a Golden Gate diamond ATR accessory. Solution
electronic absorption spectra were recorded on a Varian-Cary
5000 spectrophotometer. Electrospray mass spectra were
recorded using a Finnigan MAT LCQ mass spectrometer.
HPLC was carried out using an intelligent pump, detector,
integrator on a Hewlett Packard S1100 instrument using
Chiralcel OD-H or AD-H columns. Optical rotations
were measured using a Perkin Elmer Polarimeter 341,
sodium lamp, 1 dm cuvette lengths, c in g per 100 mL.
The circular dichroism (CD) spectrum of ligand H22 was
recorded on a DS62 spectropolarimeter (Aviv Associates,
Lakewood, NJ) using Chirascan software (Applied Biophysics
Ltd, Leatherhead, UK).
[iPr2EtNH]n Cu2I3 n
H22 (10.2 mg, 0.02 mmol) was dissolved in THF (0.8 cm3) in a
screw-capped vial containing a stir bar at room temperature.
CuI (0.04 mmol, 2.0 equiv.) was added in one portion, and the
resulting brown suspension was stirred for 30 min. Diisopropyl-
ethylamine (2.0 equiv.) was added by syringe, and the
mixture was stirred for another 10 min. After the addition of
nitromethane (0.3 cm3), the resulting pale-green solution was
filtered. The filtrate was transferred to a small vial and diethyl
ether was allowed to diffuse slowly into the solution over a
period of 3 days. X-Ray quality colourless crystals formed.
ESI-MS (MeOH–H2O): m/z 130.2 [iPr2EtNH]+ (calc. 130.2).
Ligand H21 was prepared as previously reported.34
(1S,2S)-(ꢀ)-1,2-Diphenylethane-1,2-diamine (Fluka) and
3-ethoxysalicylaldehyde were used as received (Sigma-Aldrich).
H22
A
solution of (1S,2S)-(ꢀ)-1,2-diphenylethane-1,2-diamine
(0.42 g, 2.0 mmol) in MeOH (10 cm3) was added dropwise
to a stirred solution of 3-ethoxysalicylaldehyde (0.67 g,
4.0 mmol) in MeOH (20 cm3). The resulting mixture was
heated at reflux for 2 h. After cooling to room temperature,
solid NaBH4 (0.38 g, 10.0 mmol) was added in small portions
over a period of 1 h. The resulting colourless solution was
allowed to stir at room temperature overnight, after which, the
solvent was removed in vacuo, and water (100 cm3) added, and
extracted with CHCl3 (3 ꢂ 50 cm3). The combined organic
solutions were washed with water and brine, and dried
over anhydrous Na2SO4. The solution was filtered and
concentrated under reduced pressure to give a colourless oil,
which was purified by column chromatography (SiO2, hexane–
EtOAc 4 : 1 with 5% MeOH). H22 was isolated as a white solid
(0.87 g, 85%). mp 78–80 1C. 1H NMR (500 MHz, CDCl3)
d/ppm 7.16 (overlapping, 6H, HB3+B4), 6.98 (d, J = 7.6 Hz,
4H, HB2), 6.75 (d, J = 8.0 Hz, 2H, HA4), 6.65 (t, J = 7.8 Hz,
1.33[Cu(2)]ꢃ0.67H22
H22 (5.1 mg, 0.01 mmol) was dissolved in CH2Cl2–EtOH
(1.5 cm3, 1 : 2, v/v) in a screw-capped vial containing a stirring
bar. CuCl (0.02 mmol, 2.0 equiv.) was added in one portion,
and the brown suspension was stirred at room temperature for
30 min, after which it was filtered. Solvent from the filtrate was
allowed to evaporate slowly at room temperature and
after one week, yielded brown block-like crystals. ESI-MS
(CH2Cl2–MeOH): m/z 596.1 [M
+
Na]+ (base peak,
calc. 596.2), 513.4 [H22 + H]+ (calc. 513.3).
Crystal structure determinations
2H, HA5), 6.48 (d, J = 7.5 Hz, 2H, HA6), 4.07 (q, J = 7.1 Hz,
Data were collected on Bruker-Nonius Kappa CCD or Stoe
IPDS diffractometers; data reduction, solution and refine-
ment used the programs COLLECT,45 SIR92,46 DENZO/
SCALEPACK47 and CRYSTALS,48 or Stoe IPDS software49
and SHELXL97.50 Structures have been analyzed using
Mercury v. 2.2.51
CH2CH3
4H, HCH CH ), 4.06 (q, J = 6.9 Hz, 4H, H
), 3.88
2
3
(s, 2H, Hb), 3.79 (d, J = 13.4 Hz, 2H, Ha1), 3.55 (d, J =
13.4 Hz, 2H, Ha2), 1.44 (t, J = 7.0 Hz, 6H, HCH CH ); 13C
NMR (126 MHz, CDCl3) d/ppm 147.0 (CA3), 146.6 (CA2),
138.7 (CB1), 128.5(CB2/B3), 128.3 (CB2/B3), 127.8 (CB4), 123.9
(CA1), 121.1 (CA6), 119.1 (CA5), 112.0 (CA4), 67.8 (Cb), 64.5
2
3
(CCH CH ), 49.5 (C ), 15.2 (C
); IR (solid, cmꢀ1) 3264w,
a
CH2CH3
2
3
[Cu(2)]
2974w, 2892w, 1585m, 1469s, 1393m, 1251s, 1230s, 1113m,
1068s, 1036s, 954m, 866m, 836m, 770s, 738s, 698s; UV/VIS
max/nm (2.19 ꢂ 10ꢀ5 mol dmꢀ3, THF) 240 (e/103 dm3 molꢀ1
C32H34CuN2O4, m = 574.18, green needle, monoclinic, space
group C2, a = 20.1947(8), b = 14.0122(8), c = 9.4085(5) A,
l
cmꢀ1 7.2), 264 sh (4.4), 290 (3.4); ESI-MS (MeOH) m/z 513.4
b = 96.926(4)1, U = 2642.9(2) A3, z = 4, Dc = 1.443 Mg mꢀ3
,
[M + H]+ (base peak, calc. 513.3), 535.3 [M + Na]+
m(Mo-Ka) = 0.868 mmꢀ1, T = 123 K. Total 76 654
reflections, 12 023 unique, Rint = 0.041. Refinement of 8030
reflections (354 parameters) with I 4 2s(I) converged at
final R1 = 0.0266 (R1 all data = 0.0403), wR2 = 0.0281
(wR2 all data = 0.0359), gof = 1.069.
(calc. 535.3). Found
C
73.04,
H
7.12,
N
4.92%;
C32H36N2O4ꢃ0.7H2O requires C 73.17, H 7.18, N 5.33%.
20
[a]D = ꢀ8.3 (c = 0.5, CH2Cl2). The CD spectrum of the
ligand is shown in Fig. S1, ESIw.
ꢁc
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[iPr2EtNH]n Cu2I3 n
(R)-2-Nitro-1-(3-nitrophenyl)ethanol
C8H20Cu2I3N, m = 638.06, colourless plate, monoclinic, space
group P21/n, a = 8.4552(2), b = 17.3368(4), c = 10.8328(2) A,
1H NMR (400 MHz, CDCl3) d/ppm 8.32 (s, 1H, HAr), 8.23
(m, 1H, HAr), 7.77 (d, J = 7.6 Hz, 1H, HAr), 7.62 (t, J =
8.0 Hz, 1H, HAr), 5.61 (m, 1H, HCHOH), 4.60 (d, J = 3.2 Hz,
b = 95.462(1)1, U = 1580.73(6) A3, z = 4, Dc = 2.681 Mg mꢀ3
,
m(Mo-Ka) = 8.521 mmꢀ1, T = 123 K. Total 69 573
reflections, 7681 unique, Rint = 0.032. Refinement of 5956
reflections (127 parameters) with I 4 2s(I) converged at final
R1 = 0.0178 (R1 all data = 0.0271), wR2 = 0.0167 (wR2 all
data = 0.0276), gof = 1.0936.
1H, HCH ), 4.50–4.70 (m, 1H, HOH), 3.15 (d, 1H, J = 4.0 Hz,
2
HCH ). Enantiomeric excess (HPLC, 85
: 15 heptane–
2
isopropanol, 0.8 mL minꢀ1, 250 nm): major enantiomer
Tr = 18.2 min, major enantiomer Tr = 20.9 min; 91% ee;
20
[a]D ꢀ32.0 (c = 0.5, CH2Cl2).35
(R)-1-(4-cyanophenyl)-2-nitroethanol
1.33[Cu(2)]ꢃ0.67H22
C64H69.34Cu1.33N4O8, m = 1107.10, brown block, monoclinic,
1H NMR (400 MHz, CDCl3) d/ppm 7.71 (d, J = 8.0 Hz, 2H,
HAr), 7.56 (d, J = 8.0 Hz, 2H, HAr), 5.55 (m, 1H, HCHOH),
space group C2, a = 20.412(4), b = 13.926(3), c = 9.434(2) A,
4.56 (m, 2H, HCH ), 3.08 (br, 1H, HOH). Enantiomeric excess
2
b = 97.94(3)1, U = 2656.0(10) A3, z = 2, Dc = 1.385 Mg mꢀ3
,
(HPLC, 80 : 20 heptane–isopropanol, 0.8 mL minꢀ1, 250 nm);
m(Mo-Ka) = 0.605 mmꢀ1, T = 173(2) K. Total 53 792
reflections, 8697 unique, Rint = 0.0371. Refinement of 8662
reflections (371 parameters) with I 4 2s(I) converged at final
R1 = 0.0396 (R1 all data = 0.0397), wR2 = 0.1288 (wR2 all
data = 0.1289), gof = 1.127.
major enantiomer Tr = 13.5 min, minor enantiomer Tr =
15.6 min; 90% ee; [a]D ꢀ32.8 (c = 0.50, CH2Cl2).52
20
(R)-2-Nitro-1-(pyridin-3-yl)ethanol
1H NMR (400 MHz, CDCl3) d/ppm 8.62 (s, 1H, Hpy), 8.57
(d, J = 5.2 Hz, 1H, Hpy), 7.80 (m, 1H, Hpy), 7.36 (dd, J = 7.6,
4.8 Hz, 1H, Hpy), 5.54 (dd, J = 9.6, 3.2 Hz, 1H, HCHOH), 4.64
Typical procedure for asymmetric Henry reaction
(dd, J = 13.2, 9.6 Hz, 1H, HCH ), 4.56 (dd, J = 13.2, 3.6 Hz,
2
This procedure corresponds to entry 14 in Table 3. H22
(5.1 mg, 0.010 mmol, 0.050 equiv.) was dissolved in THF
(0.4 cm3) contained in a screw-capped vial equipped with a stir
bar at room temperature. CuI (3.8 mg, 0.020 mmol, 0.10 equiv.)
was added in one portion and the resulting brown
suspension was stirred for 30 min. Diisopropylethylamine
(1.3 mg, 0.010 mmol, 0.050 equiv.) was then added by syringe,
and the mixture stirred for a further 10 min. After cooling to
273 K, nitromethane (0.13 cm3, 1.0 mmol, 5.0 equiv.) and
4-nitrobenzaldehyde (30 mg, 0.2 mmol, 1.0 equiv.) were added
sequentially. The mixture was then stirred at 273 K for 12 h
after which the volatile components were removed under
reduced pressure and the crude product purified by column
chromatography (SiO2, hexane–EtOAc, 3 : 1 v/v) to give the
nitroaldol product as a pale-yellow solid (42 mg, 99%). (R)-2-
1H, HCH ), 4.7 (br, 1H, HOH). Enantiomeric excess: (HPLC,
2
75 : 25 heptane–isopropanol, 0.7 mL minꢀ1, 250 nm); major
enantiomer Tr = 15.2 min, minor enantiomer Tr = 28.7 min;
91% ee; [a]D ꢀ38.6 (c = 0.6, CH2Cl2).53
20
(R)-2-Nitro-1-(pyridin-4-yl)ethanol
1H NMR (400 MHz, CDCl3) d/ppm 8.62 (dd, J = 4.8, 1.6 Hz,
2H, Hpy), 7.37 (m, 2H, Hpy), 5.50 (dd, J = 7.6, 4.8 Hz, 1H,
HCHOH), 4.58 (m, 2H, HCH ), 3.70 (br, 1H, HOH). Enantiomeric
2
excess: (HPLC, 75 : 25 heptane–isopropanol, 0.7 mL minꢀ1
,
220 nm); major enantiomer Tr = 11.8 min, minor enantiomer
Tr = 14.4 min; 92% ee; [a]D ꢀ31.2 (c = 0.7, CH2Cl2).54
20
(2R,3E)-1-Nitro-4-phenylbut-3-en-2-ol
1
1H NMR (400 MHz, CDCl3) d/ppm 7.38 (m, 5H, HAr),
6.80 (d, J = 16.0 Hz, 1H, HArCHQCH), 6.15 (dd, J = 16.0,
Nitro-1-(4-nitrophenyl)ethanol: H NMR (400 MHz, CDCl3)
d/ppm 8.27 (d, J = 8.8 Hz, 2H, HAr), 7.63 (d, 2H, J = 8.4 Hz,
HAr), 5.61 (m, 1H, HCHOH), 4.61 (dd, J = 14.0, 8.4 Hz, 1H,
8.0 Hz, 1H,
H
ArCHQCH), 5.06 (m, 1H, HCHOH), 4.53
(m, 1H, HCH ), 2.60 (br, 1H, HOH). Enantiomeric excess:
(HPLC, 80
20 heptane–isopropanol, 0.6 mL minꢀ1
CH2
HCH ), 4.56 (dd, J = 13.6, 4.0 Hz, 1H, H ), 3.14 (d, J =
2
2
4.0 Hz, 1H, HOH). Enantiomeric excess (HPLC, 85 : 15,
heptane–isopropanol, 0.8 mL minꢀ1, 230 nm): major enantiomer
Tr = 18.8 min, minor enantiomer Tr = 23.6 min; 92% ee;
:
,
250 nm); minor enantiomer Tr = 28.0 min, major enantiomer
20
Tr = 31.8 min; 95% ee; [a]D ꢀ7.4 (c = 0.25, CH2Cl2).27
20
[a]D ꢀ31.2 (c = 0.6, CH2Cl2). The absolute configuration of
(R)-1-Nitro-3-phenylpropan-2-ol
the Henry product was assigned as R by comparison of the
optical rotation with literature data.16
1H NMR (400 MHz, CDCl3) d/ppm 7.34 (m, 5H, HAr), 4.56
(m, 1H, HCHOH), 4.42 (m, 2H, HCH NO ), 3.05 (m, 1H, HOH),
2
2
(R)-2-Nitro-1-(2-nitrophenyl)ethanol
2.87 (dd, J = 16.0, 8.0 Hz, 2H, HArCH ). Enantiomeric excess:
2
(HPLC, 90 : 10 heptane–isopropanol, 0.8 mL minꢀ1, 210 nm);
1H NMR (400 MHz, CDCl3) d/ppm 8.08 (dd, J = 8.0, 1.2 Hz,
1H, HAr), 7.96 (dd, J = 8.0, 1.2 Hz, 1H, HAr), 7.75 (m, 1H,
HAr), 7.55 (m, 1H, HAr), 6.05 (dt, J = 8.8, 2.4 Hz, 1H,
major enantiomer Tr = 20.6 min, minor enantiomer Tr =
20
26.2 min; 90% ee; [a]D +5.2 (c = 0.20, CH2Cl2).55
HCHOH), 4.88 (dd, J = 13.6, 2.2 Hz, 1H, HCH ), 4.56
2
(R)-1-Cyclohexyl-2-nitroethanol
(dd, J = 13.6, 9.2 Hz, 1H, HCH ), 3.17 (d, J = 4.4 Hz, 1H,
2
HOH). Enantiomeric excess (HPLC, 85
:
15 heptane–
1H NMR (400 MHz, CDCl3) d/ppm 4.48 (dd, J = 13.2, 3.2
isopropanol, 0.8 mL minꢀ1, 250 nm): major enantiomer
Hz, 1H, HCH NO ), 4.41 (dd, J = 13.2, 8.8 Hz, 1H, H
),
CH2NO2
2
2
Tr = 12.3 min, minor enantiomer Tr = 14.2 min; 95% ee;
20
4.10 (m, 1H, HCHOH), 2.44 (d, J = 5.2 Hz, 1H, HOH), 1.80
[a]D +206.6 (c = 0.5, CH2Cl2).27
(m, 3H, HCy), 1.68 (m, 2H, HCy), 1.46 (m, 1H, HCy), 1.19
ꢁc
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(m, 5H, HCy). Enantiomeric excess: (HPLC, 97 : 3 heptane–
isopropanol, 0.8 mL minꢀ1, 210 nm); major enantiomer
Tr = 28.6 min, minor enantiomer Tr = 30.8 min; 88% ee;
20
[a]D ꢀ15.8 (c = 1.0, CH2Cl2).16
(R)-1-Nitrohexan-2-ol
1H NMR (400 MHz, CDCl3) d/ppm 4.43 (dd, J = 12.8,
CH2NO2
2.8 Hz, 1H, HCH NO ), 4.37 (dd, 1H, J = 12.4, 8.4 Hz, H
),
2
2
4.32 (m, 1H, HCHOH), 2.52 (d, J = 4.8 Hz, 1H, HOH), 1.43
(m, 6H, HCH ), 0.92 (t, J = 6.4 Hz, 3H, H ). Enantiomeric
CH3
2
excess: (HPLC, 98 : 2 heptane–isopropanol, 0.6 mL minꢀ1
,
210 nm); major enantiomer Tr = 39.0 min, minor enantiomer
Tr = 50.5 min; 94% ee; [a]D ꢀ9.2 (c = 0.6, CH2Cl2).16
20
Results and discussion
Syntheses and characterization of H22 and [Cu(2)]
Fig. 1 Molecular structure of one of the two independent molecules
(molecule A) of [Cu(2)] with ellipsoids plotted at the 50% probability
level, and H atoms omitted. Selected bond parameters for molecule A:
Cu1–N1 = 2.023(2), Cu1–O1 = 1.917(1) A; N1–Cu1–O1 = 94.24(5)1,
N1–Cu1–N1a = 84.01(8)1, O1–Cu1–O1a = 93.57(6)1, N1–Cu1–O1a =
The reduced Schiff base H22 was prepared by routine metho-
dology involving the condensation of 3-ethoxysalicylaldehyde
with (1S,2S)-(ꢀ)-1,2-diphenylethane-1,2-diamine followed by
reduction of the intermediate bis(imine) by NaBH4. The
electrospray mass spectrum of the compound exhibited a base
peak at m/z 513.4 assigned to [M + H]+ and a higher mass
160.69(5)1. For molecule B: Cu2–N2
= 2.024(1), Cu2–O3 =
1.923(1) A; N2–Cu2–O3 = 93.55(5)1, N2–Cu2–N2b = 85.23(8)1,
O3–Cu2–O3b = 89.80(6)1, O3b–Cu2–N2 = 168.69(5)1. Symmetry
codes: a = 1 ꢀ x, y, 1 ꢀ z; b = 1 ꢀ x, y, ꢀz.
peak at m/z 535.3 arising from [M + Na]+. The H and 13C
1
NMR spectra were assigned by 2D techniques and were in
complete accord with the structure shown in Scheme 1. The
signal for proton HA4 was assigned from a NOESY cross peak
to the resonance for the ethyl CH2 group, and that for HB2
from the NOESY cross peak to the signal for Hb.
The diastereotopic protons Ha appear as two doublets (J =
13.4 Hz) at d 3.55 and 3.79 ppm. The signal assigned to the
ethyl CH3 groups appears as a clean triplet (d 1.44 ppm), but
the resonances for the ethyl CH2 groups appear as two over-
lapping quartets (d 4.07 and 4.06 ppm), indicating that these
methylene groups sense the presence of the stereogenic centers.
The CD spectrum of H22 is shown in Fig. S1, ESIw.
The reaction of H22 with copper(II) acetate in methanol
resulted in the formation of pale green [Cu(2)]. The base peak
in the electrospray mass spectrum (m/z 596.1) corresponded to
[M + Na]+ and exhibited the corrected isotopologue distri-
bution for this ion. X-Ray quality crystals of [Cu(2)] were
obtained by slow diffusion of Et2O into an EtOH–CHCl3
solution of the complex over a period of two weeks.
The complex crystallizes in the chiral space group C2. The
asymmetric unit contains two crystallographically independent,
but structurally similar, half-molecules (labelled A and B).
The structure of molecule A is shown in Fig. 1, and selected
bond parameters for both molecules are given in the figure
caption. In molecule A, atom Cu1 resides on the special
position 0, y, 1/2, while in molecule B, atom Cu2 is sited on
the special position 0, y, 0. Since these correspond to the Cu
atoms being on 2-fold axes, the ethyl groups necessarily point
up and down on either side of the coordination plane.
Molecules of [Cu(2)] stack in columns that run parallel to
the c-axis and as a consequence of the crystal symmetry, all
Cuꢃ ꢃ ꢃCu non-bonded separations along the stack are equal
(4.7429(3) A). The molecular structure differs from that of
[Cu(1)]34,56 in two respects. Firstly, the O,O0,O00,O00 0-cavity in
[Cu(1)] acts as a host for a water molecule. Secondly, there is
face-to-face stacking of pairs of [Cu(1)] molecules with a
non-bonded Cuꢃ ꢃ ꢃCu separation of 3.816(1) A; although the
overall packing involves stacking of pairs, the second CuꢃꢃꢃCu
separation is significantly longer than the first (5.642(1) A).
Catalyst screening: copper(II) salts
In our previous studies34 of the asymmetric Henry reaction, we
tested the catalytic activity of three pre-prepared chiral
copper(II) complexes. We concluded that [Cu(1)], which
contains a reduced Schiff base ligand, gave better yields and
enantioselectivities in the reaction shown in Scheme 2 than two
complexes which contained the related imine ligands. The
catalysts were tested in the absence and presence of added
metal salts, and we noted that the activity was enhanced when
a second equivalent of Cu(OAc)2 was added to the catalyst
[Cu(1)].
The catalytic tests described below were designed to address
a number of points, and all focused on the asymmetric Henry
reaction depicted in Scheme 2. The enantiomeric excess of the
product was determined by HPLC. All the reactions detailed
in Tables 1 and 2 were carried out on a 0.20 mmol scale with
5 mol% of H22 and 5 mol% of metal salt at a 0.5 mol dmꢀ3
concentration, and using 5.0 equivalents of nitromethane in
the solvents stated in the tables. The absolute configuration of
the b-hydroxynitroalkane was assigned as (R) by comparison
with the optical rotation in the literature (see Experimental
section). We initially looked at the effects of ligand
modification, starting with a comparison of the performances
of H21 and H22 in the presence of Cu(OAc)2 in ethanol
(Table 1, entries 1 and 2). Both yield and enantioselectivity
are enhanced with the new reduced Schiff base H22. Entry 3 in
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Table 1 Results for initial screening using ligand H22 in the catalytic
asymmetric Henry reaction shown in Scheme 2
confirm that the acetate salt gives the highest yield and
enantioselectivity of those salts screened. A comparison of
screening experiments 2 and 7–10 (Table 1) illustrates the
effects of solvent on catalyst performance. Use of either
ethanol or THF results in excellent yields of the b-hydroxynitro
derivative. At 295 K, the enantioselectivity is optimized in
THF (86% ee), and this is little affected when the reaction is
carried out at 273 K over the same 18 hour period.
Entry Ligand Metal salt Solvent T/K Time/h Yielda (%) eeb (%)
1
2
3
4
5
6
7
8
H21
H22
H22
H22
H22
H22
H22
H22
H22
H22
H22
Cu(OAc)2 EtOH 295 60
Cu(OAc)2 EtOH 295 18
None EtOH 295 18
Cu(OTf)2 EtOH 295 18
86
98
42
o5
o5
40
65
40
47
95
92
23
70
0
n.d.c
n.d.
6
CuCl2
CuSO4
EtOH 295 18
EtOH 295 48
Previously, we have shown that both yield and enantio-
selectivity of the asymmetric Henry reaction in Scheme 2 are
enhanced when a second equivalent of Cu(OAc)2 is added to
the [Cu(1)] catalyst.34 Having established that yield and
enantioselectivity in the chosen test reaction were optimized
when using H22, Cu(OAc)2 in THF at 295 K, we screened a
series of catalytic runs in the presence of different metal salts
(Table 2). In each run, H22 was dissolved in THF and one
equivalent of Cu(OAc)2 was added. After B10 minutes, one
equivalent of the second metal salt was added, and the mixture
was stirred at 295 K for B30 minutes. The reagents for the
asymmetric Henry reaction in Scheme 2 were then added and
the reaction continued as described in the experimental section.
A comparison of the data in Table 2 with entry 10 in Table 1
reveals that the addition of the second 5 mol% of Cu(OAc)2
has only a small influence on the yield and enantioselectivity.
No enhancement of catalytic activity was observed upon the
addition of the other metal salts screened.
Cu(OAc)2 MeOH 295 18
Cu(OAc)2 Toluene 295 18
Cu(OAc)2 CH2Cl2 295 18
55
71
60
86
85
9
10
11
Cu(OAc)2 THF
Cu(OAc)2 THF
295 18
273 18
a
b
Isolated yield after chromatographic purification. Enantiomeric
excess was determined by HPLC using a Chiralcel OD-H column.
c
n.d. = not determined.
Table
2 Results of catalytic screening using ligand H22 and
Cu(OAc)2 in the presence of a second metal ion in the asymmetric
Henry reaction shown in Scheme 2a
Entry Second metal salt added Time/h Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OTf)2
CuCl
Pd(OAc)2
Ni(OAc)2
Co(OAc)2
KBr
18
48
65
24
16
16
24
16
94
o5
72
86
90
91
48
65
84
n.d.d
82
68
21
0
6
2
Catalyst screening: copper(I) salts
NaI
a
While the vast majority of copper-based catalysts for the
asymmetric Henry reaction involve copper(II),10,14–28,30–32,34,37
copper(I)-containing systems have also proved active.29,33,35,36
An initial test using CuCl with H22 (1 : 1, 5 mol%) in ethanol
(entry 1, Table 3) showed promising enantioselectivity for the
reaction in Scheme 2, and this was enhanced (albeit at the
expense of yield) by running the reaction in THF (entry 2,
Table 3). Significantly better results were obtained when the
loading of CuCl was increased to 10 mol%, the ligand H22
being present at a concentration of 5 mol%. Under these
conditions, an 88% yield of the b-hydroxynitro derivative was
obtained with 91% ee. We repeated the reactions using CuBr
All reactions were carried out on a 0.20 mmol scale with 5 mol% of
H22 and of Cu(OAc)2, and 5 mol% of the second metal salt at a 0.5 M
concentration using 5.0 equivalents of nitromethane in THF at 295 K.
b
c
Isolated yield after chromatographic purification. Enantiomeric
excess was determined by HPLC using a Chiralcel OD-H column.
d
n.d. = not determined.
Table 1 confirms that, in the absence of Cu(OAc)2, the
reaction is not enantioselective.
Retaining a common solvent (ethanol), metal ion (Cu2+
)
and ligand (H22), we next looked at the effects of varying the
anion. The results summarized in entries 2 and 4–6 in Table 1
Table 3 Results of catalytic screening using ligand H22 with copper(I) salts in the asymmetric Henry reaction shown in Scheme 2a
Entry
Metal salt
Loading of metal/mol%
Solvent
T/K
Time/h
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuBr
CuBr
CuI
CuI
CuI
CuI
CuI
5
5
10
5
10
5
10
10
10
10
10
10
10
10
EtOH
THF
THF
THF
THF
295
295
295
295
295
295
295
295
295
295
295
295
295
273
48
65
65
65
65
65
72
65
65
65
65
2
61
34
88
32
o5
64
88
27
36
54
o5
99
98
99
81
90
91
72
n.d.d
93
94
15
9
74
n.d.
87
90
92
THF
THF
Toluene
CH2Cl2
1,4-Dioxane
MeCN
THF
9
10
11
12e
13f
14f
CuI
CuI
CuI
CuI
THF
THF
2
12
a
All reactions were performed on a 0.20 mmol scale with 5 mol% of ligand at a 0.5 M concentration using 5.0 equivalents of CH3NO2 in the
b
solvent indicated. Isolated yields after chromatographic purification. Enantiomeric excess determined by HPLC using a Chiralcel OD-H
d
column. n.d. = not determined. 10 mol% Pr2EtN was added. 5 mol% Pr2EtN was added.
c
e
i
f
i
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or CuI in place of CuCl, with H22 : CuX ratios of 1 : 1 and 1 : 2.
Entries 4–7 in Table 3 show that while the bromide gave poor
results, a catalyst system involving 5 mol% H22 and 10 mol%
CuI was highly effective. The use of THF as solvent appears to
be preferable to the other solvents tested (entries 7–11,
Table 3). Final tuning of the reaction conditions involved
the addition of Hunig’s base (diisopropylethylamine) and
lowering of both the reaction time and temperature
(entries 12–14, Table 3).
ESI mass spectrum of [Cu(2)] exhibits a base peak at m/z 596.1
corresponding to [M + Na]+ and no other peaks with
m/z 4 443, the mass spectrum of the crystals showed a base
peak at 596.1, and a peak with about one-third its intensity at
m/z 513.4 arising from [H22 + H]+. A single crystal structure
determination confirmed the presence of 1.33[Cu(2)]ꢃ0.67H22,
that is, cocrystallization of [Cu(2)] and H22, with one-third of
the ligand sites being substituted by another [Cu(2)] molecule.
The gross structure is essentially the same as that of [Cu(2)]
described earlier, but it is noteworthy that there is no change in
conformation of the ligand upon binding of the Cu2+ ion in
the N,N0,O,O0-cavity of [2]2ꢀ. In this case, oxidation of
copper(I) to copper(II) occurs within a short time of mixing
the components of the catalyst system (entry 3, Table 3).
It is, of course, not necessarily the case that the active
catalyst in the systems listed in Table 3 contains copper(I).
Aerial oxidation to copper(II) is obviously possible with the
Schiff base ligand stabilizing this oxidation state. We therefore
attempted to crystallize species present in two of the
copper(I)-based catalyst systems. In the first, H22 and CuI
were combined in THF and the solution stirred in the presence
Extending the scope of the catalyst system
i
of Pr2EtN, followed by addition of nitromethane. X-Ray
Once we had optimized the conditions (entries 13 and 14 in
Table 3) for the enantioselective formation of (R)-2-nitro-1-
(4-nitrophenyl)ethanol, we investigated the range of asymmetric
Henry reactions to which these same conditions could be
applied. All reactions were carried out on a 0.20 mmol scale.
Fig. 3 illustrates that the conversion of aryl aldehydes with
quality colourless needles formed when Et2O was allowed to
diffuse slowly into the filtered reaction mixture. An electro-
spray mass spectrum of this product (MeOH–H2O) showed
only a peak at m/z 130.2 assigned to [iPr2EtNH]+. Structural
analysis revealed the compound to be the copper(I) salt
[iPr2EtNH]n Cu2I3 n containing polymeric anions (Fig. 2).
The structure of the polymer is similar to those found
57
58
in [K(12-crown-4)2]2n Cu4I6 n
,
[K(15-crown-5)]2n Cu4I6 n,
59
[Na(15-crown-5)]2n[Na(15-crown-5)(OH2)]2n[Cu2I4]n Cu4I6 n
60
,
[Rb(12-crown-4)2]n Cu2I3 n
,
[2,4,6-Ph3C5H2S][Cu2I3]61 and
62
[Et4N]n Cu2I3 n The chains are propagated parallel to the
crystallographic a-axis and are involved in hydrogen bonds
to the [iPr2EtNH]+ ions (N9H91ꢃ ꢃ ꢃI2 = 2.80, N9ꢃ ꢃ ꢃI2 =
3.675(1) A, N9–H91ꢃ ꢃ ꢃI2 = 1661; C3H31. . .I2ii = 3.09,
C3ꢃ ꢃ ꢃI2ii = 3.898(2) A, C3–H31ꢃ ꢃ ꢃI2ii = 1421; symmetry
code ii = ii = 2 ꢀ x, 1 ꢀ y, 1 ꢀ z). The lack of the chiral
ligand H22 in the crystallized product clearly indicates that the
latter is not the catalytically active species. Nonetheless, the
data suggest that copper(I) may survive the conditions used for
the asymmetric Henry reaction (entries 12–14, Table 3).
In the second crystallization experiment, solid CuCl was
added to a CH2Cl2–EtOH solution of H22. After being stirred
for 30 minutes, the mixture was filtered, and slow evaporation
of the solvent yielded brown block-like crystals. Whereas the
Fig. 2 Part of one polymeric chain in [iPr2EtNH]n[Cu2I3]n with
ellipsoids plotted at the 50% probability level. Symmetry codes:
i = 1 ꢀ x, 1 ꢀ y, 1 ꢀ z; ii = 2 ꢀ x, 1 ꢀ y, 1 ꢀ z. Selected bond distances:
I1–Cu1i = 2.5382(3), I1–Cu1 = 2.7280(3), I1–Cu2 = 2.7903(3),
I2–Cu1 = 2.6736(3), I2–Cu2 = 2.6764(3), I3–Cu2ii = 2.5422(3),
I3–Cu1 = 2.7841(3), I3–Cu2 = 2.7328(3), Cu1–Cu1i = 2.6276(5),
Cu1–Cu2 = 2.4900(3), Cu2–Cu2ii = 2.6378(5) A.
Fig. 3 Results of the enantioselective Henry reaction of nitromethane
and selected aldehydes under optimized reaction conditions.
(i) H22 (5 mol%), CuI (10 mol%), THF, 273 K, 12 h. (ii) H22 (5 mol%),
CuI (10 mol%), THF, 295 K, 72 h.
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electron-withdrawing substituents proceeds in high yield
and with excellent enantioselectivity (entries 1–4 in Fig. 3).
The pyridine derivatives were chosen as being representative
of simple N-heterocyclic compounds, and both undergo trans-
formation to the respective b-hydroxynitro derivative in high
yield and with high enantioselectivity (entries 5 and 6, Fig. 3).
The b-hydroxynitro derivatives of representative aliphatic
aldehydes were obtained in moderate to good yields, and with
excellent, or still acceptable, enantioselectivities. The reaction
conditions proved not to be applicable to simple aromatic
aldehydes (e.g. benzaldehyde) or aromatic aldehydes with
electron-donating substituents (e.g. Cl, OMe, Me).
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We have tuned the components of a catalytic system for the
asymmetric Henry reaction involving the reduced Schiff base
ligand H22 and copper salts. Reaction conditions for the
conversion of 4-nitrobenzaldehyde to 2-nitro-1-(4-nitrophenyl)-
ethanol have been optimized catalyst 5 mol% H22, 10 mol%
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in 99% yield and 90–92% ee. These catalytic conditions
are effective for other aromatic aldehydes containing
electron-withdrawing substituents, and for pydridyl aldehydes;
representative aliphatic aldehydes were converted to the
respective b-hydroxynitro derivatives with good enantio-
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those containing electron-releasing substituents.
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