Tridentate ligands derived from L-tert-Leucine for the Cu(II) mediated asymmetric Henry reaction

Article abstract of DOI:10.3906/kim-1009-15

Chiral tridentate Schiff base ligands were prepared from L-tert-Leucine and used as catalysts in the asymmetric Henry reaction in the presence of Cu(II) ions. Moderate enantiomeric excesses (up to 66%) and yields (up to 76%) of the desired β-nitroalcohols were obtained. TUeBITAK.

Full text of DOI:10.3906/kim-1009-15

Turk J Chem
35 (2011) , 361 – 374.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1009-15
Tridentate ligands derived from L-tert-Leucine for the
Cu(II) mediated asymmetric Henry reaction
Neslihan KORKMAZ, Demet ASTLEY, Stephen T. ASTLEY∗
Department of Chemistry, Faculty of Science, Ege University,
˙
35100, Bornova, Izmir-TURKEY
e-mail: astleys@yahoo.co.uk
Received: 08.09.2010
Chiral tridentate Schiff base ligands were prepared from L-tert-Leucine and used as catalysts in the
asymmetric Henry reaction in the presence of Cu(II) ions. Moderate enantiomeric excesses (up to 66%) and
yields (up to 76%) of the desired β -nitroalcohols were obtained.
Key Words: Asymmetric Henry reaction, chiral Schiff base, L-tert-Leucine, amino alcohol, tridentate
ligand
Introduction
The nitroaldol or Henry reaction is one of the classical named reactions in organic synthesis. Essentially the
coupling of the nucleophile generated from a nitroalkane with a carbonyl electrophile, it has been a widely used
transformation since its discovery in 1895.1 The resulting product of this reaction is a β-nitroalcohol, which is
a versatile intermediate in synthetic organic chemistry.
The Henry reaction may be catalyzed or promoted by many different catalysts, including inorganic bases2
and organocatalysts;3 however, much recent effort has been focused on the development of various metal-based
catalysts. Included in this research effort was the first asymmetric version of the Henry reaction. This was
reported by Shibasaki and coworkers in 1992 and involved a lanthanide-based catalyst.4 Subsequent work has
focused to a significant extent on chiral complexes of zinc5,6 and copper.7,8
As part of an ongoing investigation into the structure and reactivity of tridentate Schiff base ligands
and complexes derived from L-tert-Leucine, we recently reported the structure of a highly novel nickel complex
derived from ligand A (Figure 1), which contained an unprecedented anti-skew carboxylate bridging group.9
∗Corresponding author
361

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
O
N
ONa
OH
HO
A
Figure 1. The structure of ligand A.
While carrying out these studies, we became aware that copper complexes of closely related Schiff bases
ligands were becoming of increasing importance in the asymmetric Henry reaction.10−15 For example, Wang
(B),16 Punniyamurthy (C),17 and Mao (D)18 (Figure 2) independently prepared tridentate amino alcohol
based Schiff base
R'
R
N
R
N
OH
HO
OH
OH
R
R
B
C
N
OH
HO
D
Figure 2. Ligands B, C, and D.
362

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
ligands starting from chiral amino acids or amino alcohols. It was determined that the solid state structure
of Cu(II) complexes of ligands B and C consists of a dimeric structure where each copper center has square
planar geometry and the OH groups originating from the amino alcohol moiety occupy bridging positions. We
were interested in employing derivatives of ligand A in this reaction to see if we could utilize the bulkiness of
the tert-butyl group present in L-tert-Leucine to good effect in this type of reaction. Therefore we prepared a
series of ligands from L-tert-Leucine as can be seen in Figure 3.
Ar
R2
R2
CHO
OH
N
Ar
Ar
MeOH
RT
Ar
+
OH
H2N
OH
OH
R1
R1
3a: R1= H,
R2= H,
Ar= Ph
Ar= Ph
1a: Ar= Ph
2a: R1= H,
R2= H
1b: Ar= 3-Me-Ph
1c: Ar= 4-Me-Ph
3b:
R1= H,
R2= t-Bu,
R2= Br,
2b: R1= H,
R2= t-Bu
R2= Br
R2= H
3c: R1= H,
Ar= Ph
2c: R1= H,
3d: R1= -OH, R2= H,
3e: R1= -OBn, R2= H,
3f: R1= -OMe, R2= H,
Ar= Ph
2d: R1= -OH,
2e: R1= -OBn,
2f: R1= -OMe,
2g: R1= H,
Ar= Ph
R2= H
R2= H
R2= -OH
R2= t-Bu
Ar= Ph
3g: R1= H,
R2= -OH,
Ar= Ph
3h: R1= t-Bu, R2= t-Bu,
Ar= Ph
2h: R1= t-Bu,
2i: 2-OH-naphtaldehyde
3i: R1= H,
R2= H,
R2= H,
Ar= 3-Me-Ph
Ar= 4-Me-Ph
Ar= Ph
3j: R1= H,
3k: 2-naphthol
Figure 3. Preparation of Schiff base ligands.
Experimental
All 1 H-NMR and 13 C-NMR spectra were recorded using a Varian AS 400+ Mercury FT NMR spectrometer at
ambient temperature. IR spectra were recorded on a Perkin Elmer 100 FTIR spectrometer. The enantiomeric
excesses of the Henry reaction products were determined by HPLC using a chiralcel OD-H column. Optical
rotations were determined using a Rudolph Research Analytical Autopol I automatic polarimeter. Absolute
configurations of the product β-nitroalcohols were determined by comparison of [α]2D5 values with literature
values. 7−19 Solvents were used as received from commercial sources.
Preparation of L-tert-Leucine methyl ester hydrochloride methyl (S)-2-amino-3,3-
dimethylbutanoate hydrochloride
A solution of the L-tert-Leucine (2 mmol) in 20 mL of methanol was cooled with ice water. After cooling, 2
mL of SOCl2 was added dropwise. The resulting clear solution was then refluxed for 8 h. Evaporation of the
solvent gave a white solid. IR (KBr), 3344, 3085, 3083, 3057, 2948, 2904, 1583, 1492, 1473, 1447, 1376, 1167,
1057 cm−1
.
1 H-NMR (MeOH, δ ppm): 7.66 (d, J =8 Hz, 2 H), 7.55 (d, J =8 Hz, 2H), 7.30 (t, J =7.6 Hz,
2H), 7.20 (t, J =7.6 Hz, 2H), 7.01 (t,J = 7.6 Hz, 2H), 4.41 (br, 1H), 3.82 (s, 1H), 1.37 (br, 2H), 0.79 (s, 9H).
363

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
13 C-NMR (CDCl3 , δ ppm), 150.1, 145.5, 128.7, 127.9, 126.6, 126.4, 125.8, 80.1, 77.6, 77.3, 76.9, 63.9, 35.8,
29.3. Elemental analysis, calculated for C18 H23 NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 79.33; H, 8.54; N,
5.10%.
General procedure for the preparation of 1a-c
In a 2-necked round-bottomed flask fitted with a reflux condenser were placed Mg (20 mmol) and anhydrous
diethyl ether (20 mL). The mixture was stirred and bromobenzene derivatives (10 mmol) were added dropwise.
The reaction mixture was then refluxed for 30 min. After cooling, it was added to a mixture of methyl (S)−2-
amino-3,3-dimethylbutanoate hydrochloride (2 mmol) in 5 mL of diethyl ether as quickly as possible. The
reaction mixture was stirred for 24 h at ambient temperature and then quenched with saturated NH4 Cl in ice
water. The solution was filtered and extracted with diethyl ether. The organic phase was dried using Na2 SO4
and evaporated under vacuum and a yellow solid was obtained.
(S)-2-amino-3, 3-dimethyl-1,1-diphenylbutan-1-ol (1a)
The yellow solid was washed with cold hexane to give white crystals, 62% yield, mp = 130-133 ◦ C, IR (KBr),
.
3344, 3085, 3083, 3057, 2948, 2904, 1583, 1492, 1473, 1447, 1376, 1167, 1057, 967 cm−1 1 H-NMR (CDCl3 , δ
ppm), 7.66 (d, J =8 Hz, 2 H), 7.55 (d, J =8 Hz, 2H), 7.3 (t, J =7.6 Hz, 2H), 7.20 (t, J =7.6 Hz, 2H), 7.01
(t, J =7.6 Hz, 2H), 4.41 (br, 1H), 3.82 (s, 1H), 1.37 (br, 2H), 0.79 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 150.1,
145.5, 128.7, 127.9, 126.6, 126.4, 125.8, 80.1, 77.6, 77.3, 76.9, 63.9, 35.7, 29.3. Elemental analysis, calculated for
C18 H23 NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 79.33; H, 8.54; N, 5.10%.
(S)-2-amino-3,3-dimethyl-1,1-di m-tolylbutan-1-ol (1b)
The yellow solid was purified by column chromatography using hexane:ethyl acetate (90:10). White crystals,
36% yield, mp = 127-129 ◦ C, IR (KBr), 3408, 3337, 3036, 2954, 2948, 1602, 1480, 1447, 1381, 1301, 1167, 1137,
.
868 cm−1 1 H-NMR (CDCl3 , δ ppm), 7.47-6.91 (m, 8H), 3.80 (s, 1H), 2.38 (s, 3H), 2.31 (s, 3H), 1.52 (br, 2H),
0.80 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 149.9, 145.4, 138.3, 137.3, 128.5, 127.7, 127.4, 127.1, 126.8, 126.7,
123.7, 122.6, 80.1, 63.9, 35.7, 29.3, 21.9, 21.9. Elemental analysis, calculated for C20 H27 ON: C, 80.76; H, 9.15;
N, 4.71. Found: C, 79.64; H, 8.91; N, 4.18%.
(S)-2-amino-3,3-dimethyl-1,1-di p-tolylbutan-1-ol (1c)
The yellow solid was purified by column chromatography using hexane:ethyl acetate. White crystals, 31% yield,
mp = 117-120 ◦ C, IR (KBr), 3412, 2981, 2956, 2921, 1507, 1469.3, 1410, 1376, 1183, 804 cm−1
.
1 H-NMR
(CDCl3 , δ ppm), 7.51 (d, J = 8 Hz, 2H), 7.40 (d, J = 8 Hz, 2H), 7.09 (d, J = 8 Hz, 2H), 7.00 (d, J = 8 Hz,
2H), 3.77 (s, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 1.75 (br, 1H), 0.79 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 147.3,
142.8, 136.1, 135.7, 129.4, 128.6, 126.2, 125.6, 79.9, 63.8, 35.7, 29.4, 21.2, 21.1. Elemental analysis, calculated
for C20 H27 ON: C, 80.76; H, 9.15; N, 4.71. Found: C, 79.14; H, 8.92; N, 4.48%.
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Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
General procedure for the preparation of the chiral Schiff bases
The solution of aldehyde (1 mmol) in MeOH was added dropwise into the solution of amino alcohol (1 mmol) in
5 mL of MeOH. The reaction mixture was stirred for 2-10 h at room temperature. Evaporation of the solvent
provided a residue, which was crystallized from CH2 Cl2 :hexane to give yellow or orange crystals (59%-98%
yields).
(S)-2-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]phenol (3a)
Yellow crystals, 97% yield, mp = 174.6-176.1 ◦ C, IR (KBr), 3054, 2955, 2871, 1627, 1582, 1491, 1448, 1275,
1151, 750 cm−1 . 1H-NMR (CDCl3 , δ ppm) 12.85 (s, 1H), 8.12 (s, 1H), 7.23 (d, J = 7.6 Hz, 2H), 7.53 (d, J =
8 Hz, 2H), 7.29-7.14 (m, 6H), 7.09 (dd, J = 1.6 Hz, 7.6 Hz, 2H), 7.03 (t, J = 7.6 Hz, 2H), 6.87 (d, J = 8.4 Hz,
1H), 6.81 (t, J = 7.6 Hz, 1H), 4.08 (s, 1H), 2.83 (s, 1H), 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ ppm) 166.9, 155.8,
148.1, 131.9, 129.9, 128.4, 128.2, 127.3, 127.0, 126.8, 126.3, 126.1, 125.9, 120.9, 118.6, 117.7, 115.6. Elemental
analysis, calculated for C25 H27 O2 N: C, 80.40; H, 7.29; N, 3.75. Found: C, 79.50; H, 7.22; N, 3.80%. [α]25
=
D
+52.8 (c 0.8, CH2 Cl2).
(S)-4-tert-butyl-2-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]phenol (3b)
Yellow crystals, 90% yield, mp = 161-162 ◦ C, IR (KBr), 3599, 3054, 3033, 2960, 2901, 2871, 1633, 1594, 1493,
1449, 1265, 1184, 1059, 705 cm−1 1 H-NMR (CDCl3 , δ ppm), 8.15 (s, 1H), 7.66 (dd, J = 1.2 Hz, 7.6 Hz,
.
2H), 7.54 (dd, J = 1.2 Hz, 8.8 Hz, 2H), 7.31-7.02 (m, 7H), 6.81 (d, J = 8.4, 1H), 4.09 (s, 1H), 2.88 (br, 1H),
1.27 (s, 9H), 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 167.5, 158.5, 147.6, 145.2, 141.6, 130.1, 128.4, 128.2,
126.8, 126.6, 126.3, 125.9, 117.9, 116.5, 83.9, 80.8, 36.6, 34.1, 31.6, 29.8. Elemental analysis, calculated for
C29 H35 O2 N: C, 81.08; H, 8.21; N, 3.26. Found: C, 82.05; H, 8.09; N, 3.33%. [α]25 = -27.5 (c 0.36, CH2 Cl2).
D
(S)-4-bromo-2-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]phenol (3c)
Yellow crystals, 92% yield, mp = 185-186 ◦ C, IR (KBr), 3601, 3062, 2947, 2868, 1630, 1572, 1479, 1449, 1357,
1274, 1057, 705 cm−1
.
1 H-NMR (CDCl3 , δ ppm), 12.87 (br, 1H), 7.99 (s, 1H), 7.64 (dd, J = 1.2 Hz, 8 Hz,
2H), 7.49 (dd, J = 1.2 Hz, 8.8 Hz, 2H), 7.32-7.15 (m, 7H), 7.06 (td, J = 1.2 Hz, 7.6 Hz, 1H), 6.76 (d, J =
8.8 Hz, 1H), 4.05 (s, 1H), 2.73 (br, 1H), 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 165.5, 160.1, 146.9, 145.0,
135.3, 133.7, 128.5, 128.0, 127.0, 126.9, 126.2, 125.8, 119.9, 119.1, 110.3, 96.4, 84.2, 80.9, 36.5, 29.8. Elemental
analysis, calculated for C25 H26 O2 NBr: C, 66.37; H, 5.79; N, 3.10. Found: C, 65.71; H, 5.70; N, 3.17%. [α]25
=
D
-2.4 (c 0.83, CH2 Cl2).
(S)-3-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]benzene-1,2-diol (3d)
Yellow crystals, 97% yield, mp = 99-102 ◦ C, IR (KBr), 3420, 3059, 3035, 2958, 1635, 1599, 1543, 1516, 1464,
1449, 1239, 742 cm−1 . 1H-NMR (CDCl3 , δ ppm), 7.91 (s, 1H), 7.67-7.65 (m, 2H), 7.52-7.50 (m, 2H), 7.32-7.28
(m, 2H), 7.25-7.17 (m, 3H), 7.07-7.03 (m, 1H), 6.88 (dd, J = 2 Hz, 6.4 Hz, 1H), 6.56 (m, 2H), 4.13 (s, 1H),
3.06 (br, 1H), 0.88 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 166.2, 155.5, 146.6, 146.5, 144.9, 128.6, 128.3, 127.2,
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Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
127.0, 126.2, 125.7, 122.5, 116.9, 116.6, 81.2, 81.2, 36.6, 31.8, 22.9, 14.3. Elemental analysis, calculated for
C
25 H27 O3 N: C, 77.09; H, 6.99; N, 3.60. Found: C, 76.97; H, 7.58; N, 3.26%. [α]25 = -211.9 (c 0.71, CH2 Cl2).
D
(S)-2-(benzyloxy)-6-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]phenol (3e)
Yellow crystals, 59% yield, mp = 139-142 ◦ C, IR (KBr), 3581, 3061, 3027, 2932, 2871, 1627, 1583, 1495, 1450,
1250, 1061, 749 cm−1
.
1 H-NMR (CDCl3 , δ ppm), 8.12 (s, 1H), 7.67 (dd,J = 0.8 Hz, 7.2 Hz, 2H), 7.53 (dd,
J = 0.8 Hz, 7.6 Hz, 2H), 7.44 (d, J = 7.2 Hz, 2H), 7.38-7.14 (m, 8H), 7.03 (td, J = 1.2 Hz, 7.2 Hz, 1H), 6.88 (d,
J = 7.6 Hz, 1H), 6.74-6.65 (m, 2H), 5.13 (s, 2H), 4.09 (s, 1H), 2.87 (br, 1H), 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ
ppm), 167.1, 151.9, 147.5, 147.4, 145.1, 137.2, 128.8, 128.4, 128.1, 127.7, 126.9, 126.7, 126.3, 125.9, 123.9, 118.7,
118.2, 116.9, 83.8, 80.9, 71.4, 36.5, 29.8. Elemental analysis, calculated for C32 H33 O3 N: C, 80.14; H, 6.94; N,
2.92. Found: C, 79.05; H, 6.91; N, 2.92%. [α]2D5 = +84.5 (c 0.69, CH2 Cl2).
(S)-2-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]-6-methoxyphenol (3f)
Yellow crystals, 98% yield, mp = 182-184 ◦ C, IR (KBr), 3590, 3054, 2961, 2874, 1627, 1492, 1448, 1469, 1362,
.
1259, 1080 cm−1 1 H-NMR (CDCl3 , δ ppm), 13.53 (br, 1H), 8.09 (s, 1H), 7.66 (dd, J = 1.2 Hz, 7.6 Hz, 2H),
7.53 (dd, J = 1.2 Hz, 7.6 Hz, 2H), 7.29-7.14 (m, 5H), 7.05-7.01 (m, 1H), 6.87-6.85 (m, 1H), 6.75-6.70 (m, 2H),
4.08 (s, 1H), 3.86 (s, 3H), 2.82 (br, 1H), 1.57 (br, 1H), 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 166.9, 151.7,
148.5, 147.1, 145.1, 128.4, 128.2, 126.9, 126.7, 126.3, 125.9, 123.3, 118.3, 118.2, 114.1, 83.7, 80.9, 56.2, 36.5,
29.8. Elemental analysis, calculated for C26 H28 O3 N: C, 77.39; H, 7.24; N, 3.47. Found: C, 76.46; H, 7.06; N,
3.47%. [α]2D5 = +73.8 (c 1.22, CH2 Cl2).
(S)-2-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]benzene-1,4-diol (3g)
Orange crystals, 61% yield, mp = 179-180 ◦ C, IR (KBr), 3309, 3082, 2961, 2933, 2868, 1633, 1596, 1489, 1478,
.
1376, 1159, 1058, 702 cm−1 1 H-NMR (CDCl3 , δ ppm), 8.03 (s, 1H), 7.67 (dd, J = 1.2 Hz, 7.6 Hz, 2H), 7.52
(dd, J = 1.2 Hz, 7.2 Hz, 2H), 7.29-7.14 (m, 6H), 7.03 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 6.58 (d,
J = 2.8 Hz, 1H), 4.07 (s, 1H), 2.88 (br, 1H) 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 166.5, 154.9, 147.87,
147.3, 145.1, 128.4, 128.2, 126.9, 126.7, 126.3, 125.9, 120.5, 118.4, 117.7, 117.3, 84.1, 80.9, 36.5, 29.8. Elemental
analysis, calculated for C25 H27 O3 N: C, 77.09; H, 6.99; N, 3.60. Found: C, 76.34; H, 6.86; N, 3.51%. [α]25
=
D
+27.0 (c 0.30, CH2 Cl2).
(S)-2,4-di-tert-butyl-6-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]phenol (3h)
Yellow crystals 59% yield, mp = 155-157 ◦ C, IR (KBr), 3581, 3061, 3027, 2932, 2871, 1627, 1583, 1495, 1450,
1250, 1061, 749 cm−1
.
1 H-NMR (CDCl3 , δ ppm), 8.13 (s, 1H), 7.65 (dd, J = 1.2 Hz, 8.8 Hz, 2H), 7.53 (dd,
J = 1.2 Hz, 8.4 Hz, 2H), 7.30-7.12 (m, 7H), 7.02 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 4.06 (s, 1H), 2.92
(br, 1H), 1.39 (s, 9H), 1.27 (s, 9H), 0.85 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 167.1, 151.9, 147.5, 147.4, 145.1,
137.2, 128.8, 128.4, 128.12, 127.7, 126.9, 126.7, 126.3, 125.9, 123.9, 118.7, 118.2, 116.9, 83.8, 80.9, 71.4, 36.5,
29.8. Elemental analysis, calculated for C33 H41 O2 N: C, 80.14; H, 6.94; N, 2.92. Found: C, 79.05; H, 6.91; N,
2.92%. [α]2D5 = +23.7 (c 0.84, CH2 Cl2).
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Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
(S)-2-[(1-hydroxy-3,3-dimethyl-1,1-dim-tolylbutan-2-ylimino)methyl]phenol (3i)
Yellow crystals, 78% yield, mp = 138-141 ◦ C, IR (KBr), 3598, 3038, 2956, 2869, 1628, 1603, 1582, 1480, 1463,
.
1276, 1151, 753 cm−1 1 H-NMR (CDCl3 , δ ppm), 8.08 (s, 1H), 7.47-6.77 (m, 13H), 4.02 (s, 1H), 2.77 (br, 1H),
2.33 (s, 3H), 2.24 (s, 3H), 0.86 (s, 9H). 13 C-NMR (CDCl3 , δ ppm), 166.8, 160.9, 147.3, 145.1, 137.8, 137.5,
132.5, 131.6, 128.0, 127.9, 127.6, 127.4, 126.8, 126.7, 123.6, 123.0, 118.8, 118.6, 117.1, 96.4, 84.1, 80.8, 36.5,
29.9, 21.8, 21.9. Elemental analysis, calculated for C27 H31 O2 N: C, 80.76; H, 7.78; N, 3.49. Found: C, 79.98;
H, 7.78; N, 3.21%. [α]2D5 = +61.2 (c 0.59, CH2 Cl2).
(S)-2-[(1-hydroxy-3,3-dimethyl-1,1-dip-tolylbutan-2-ylimino)methyl]phenol (3j)
Yellow crystals, 63% yield, mp = 175-177 ◦ C, IR (KBr), 3559, 3024, 2957, 2868, 2730, 1628, 1582, 1508, 1478,
.
1463, 1369, 1275, 1065, 754 cm−1 1 H-NMR (CDCl3 , δ ppm), 12.86 (br, 1H), 8.11 (s, 1H), 7.48 (dd, J = 2 Hz,
8.4 Hz, 2H), 7.37 (dd, J = 2 Hz, 8.8 Hz, 2H), 7.25-7.21 (m, 2H), 7.09-6.98 (m, 4H), 6.86 (d, J = 7.6 Hz, 2H),
6.79 (td, J = 0.8 Hz, 7.6 Hz, 2H), 4.01 (s, 1H), 2.70 (br, 1H), 2.69 (s, 3H), 2.18 (s, 3H), 0.84 (s, 9H). 13 C-NMR
(CDCl3 , δ ppm), 166.8, 160.9, 144.6, 142.5, 136.3, 136.1, 132.6, 131.8, 129.1, 128.8, 126.1, 125.8, 118.8, 118.7,
117.1, 83.9, 80.74, 77.5, 77.2, 76.9, 36.5, 29.8, 21.1, 21.0. Elemental analysis, calculated for C27 H31 O2 N: C,
80.76; H, 7.78; N, 3.49. Found: C, 80.05; H, 7.64; N, 3.43%. [α]2D5 = -58.0 (c 0.55, CH2 Cl2).
(S)-1-[(1-hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-ylimino)methyl]naphthalen-2-ol (3k)
Yellow crystals, 84% yield, mp = 151-154 ◦ C, IR (KBr), 3197, 3054, 2960, 1626, 1596, 1543, 1524, 1493, 1368,
1349, 1194, 739, 697 cm−1 . 1H-NMR (CDCl3 , δ ppm), 8.43 (s, 1H), 7.71 (dd, J = 1.2 Hz, 8.8 Hz, 2H), 7.60
(dd, J = 1.2 Hz, 8.8 Hz, 2H), 7.56 (d, J = 8 Hz, 1H), 7.39 (td, J = 1.2 Hz, 8 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H),
7.25-7.19 (m, 4H), 7.01 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H). 13 C-NMR (CDCl3 , δ ppm) 174.0, 159.7,
146.1, 145.0, 136.9, 133.9, 129.3, 128.6, 128.3, 127.9, 127.3, 127.2, 126.6, 126.4, 125.9, 124.2, 122.9, 118.2, 106.9,
81.5, 79.6, 77.6, 77.2, 76.9, 36.8, 29.8. Elemental analysis, calculated for C29 H29 O2 N: C, 82.24; H, 6.90; N,
3.31. Found: C, 78.05; H, 6.70; N, 3.16%. [α]2D5 = -9.15 (c 0.66, CH2 Cl2).
General procedure for the asymmetric Henry reaction
To a solution of ligand 3a-k (0.01 mmol) and 1 mL of TBME at the given temperature was added Cu(OAc)2 .nH2 O
(0.01 mmol). The mixture was allowed to stir for 5 h. The aldehyde (0.1 mmol) and nitromethane (10 mmol)
were added into the solution. The progress of the reaction was monitored by TLC. After completion, the sol-
vent was evaporated and the residue was purified by column chromatography using hexane:ethyl acetate (5:1)
to afford the desired Henry product 4a-j. The enantiomeric excess values were determined by HPLC using a
Chiralcel OD-H column.
(R)-1-(4-nitrophenyl)-2-nitroethanol (4a)
White crystals, 76% yield, 1H-NMR (CDCl3 , δ ppm), 3.17 (br, 1H), 4.58 (d, J = 2 Hz, 1H), 4.60 (d, J = 6 Hz,
1H), 5.61 (m, 1H), 7.63 (m, 2H), 8.26 (m, 2H). HPLC: Chiralcel OD-H column, hexane:isopropanol (90:10), 1
367

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
mL/min, 267 nm, major enantiomer tr = 29.4 min, minor enantiomer tr = 37.6 min, 63% ee, [α]25 = -21.2 (c
D
1.23, CH2 Cl2).
(R)-1-(3-nitrophenyl)-2-nitroethanol (4b)
Yellow oil, 63% yield, 1H-NMR (CDCl3 , δ ppm), 3.51 (br, 1H), 4.63 (m, 2H), 5.61 (dd, J = 4.4, 7.6 Hz,
1H), 7.61 (t, J = 7.6 Hz, 1H), 7.78 (m, 1H), 8.19 (m, 1H), 8.30 (m, 1H). HPLC: Chiralcel OD-H column,
hexane:isopropanol (90:10), 1 mL/min, 267 nm, major enantiomer tr = 28.1 min, minor enantiomer tr = 32.5
min, 52% ee, [α]2D5 = -7.34 (c 1.1, CH2 Cl2).
(R)-1-(2-nitrophenyl)-2-nitroethanol (4c)
Brown crystals, 54% yield, 1H-NMR (CDCl3 , δ ppm), 3.35 (br, 1H), 4.56 (dd, J = 9.2, 13.6 Hz, 1H), 4.85 (dd,
J = 2.4, 14 Hz, 1H), 6.03 (d, J = 8 Hz, 1H), 7.55 (td, J = 1.6, 8.4 Hz, 1H), 7.75 (td, J = 0.8, 7.6 Hz, 1H), 7.95
(d, J = 8 Hz, 1H), 8.06 (dd, J = 1.2, 8 Hz, 1H). HPLC: Chiralcel OD-H column, hexane:isopropanol (90:10), 1
mL/min, 267 nm, major enantiomer tr = 15.9 min, minor enantiomer tr = 18.3 min, 48% ee, [α]2D5 = +123.9
(c 0.9, CH2 Cl2).
(R)-1-(2-chlorophenyl)-2-nitroethanol (4d)
Colorless oil, 25% yield, 1H-NMR (CDCl3 , δ ppm), 4.36 (dd, J = 9.6, 13.6 Hz, 1H), 4.57 (dd, J = 2.4,
13.6 Hz, 1H), 5.75 (m, 1H), 7.24 (m, 3H), 7.56 (dd, J = 2, 7.6 Hz, 1H). HPLC: Chiralcel OD-H column,
hexane:isopropanol (95:5), 1 mL/min, 267 nm, major enantiomer tr = 14.6 min, minor enantiomer tr = 15.6
min, 49% ee, [α]2D5 = -32.9 (c 0.61, CH2 Cl2).
(R)-1-(4-methylphenyl)-2-nitroethanol (4e)
Yellow oil, 18% yield, 1H-NMR (CDCl3 , δ ppm), 2.36 (s, 3H), 2.74 (br, 1H), 4.48 (dd, J = 2.8, 13.2 Hz, 1H),
4.60 (dd, J = 10.4, 13.6 Hz, 1H), 5.42 (d, J = 9.2 Hz, 1H), 7.26 (m, 4H). HPLC: Chiralcel OD-H column,
hexane:isopropanol (90:10), 1 mL/min, 267 nm, major enantiomer tr = 13.5 min, minor enantiomer tr = 17.09
min, 58% ee, [α]2D5 = -28.1 (c 0.5, CH2 Cl2).
(R)-1-(4-ethylphenyl)-2-nitroethanol (4f)
Yellow oil, 20% yield, 1H-NMR (CDCl3 , δ ppm), 1.23 (t, J = 7.6 Hz, 3H), 2.65 (q, J = 7.6 Hz, 2H), 2.86
(d, J = 3.6 Hz, 1H), 4.48 (dd, J = 3.2, 13.2 Hz, 1H), 4.50 (dd, J = 9.6, 13.2 Hz, 1H), 5.42 (m, 1H), 7.22
(m, 2H), 7.29 (m, 2H). HPLC: Chiralcel OD-H column, hexane:isopropanol (90:10), 1 mL/min, 267 nm, major
enantiomer tr = 12.3 min, minor enantiomer tr = 15.9 min, 59% ee, [α]25 = -26.2 (c 0.53, CH2 Cl2).
D
(R)-1-(4-methoxyphenyl)-2-nitroethanol (4g)
Yellow oil, 48% yield, 1H-NMR (CDCl3 , δ ppm), 2.84 (br, 1H), 3.81 (s, 3H), 4.46 (dd, J = 2.8, 12.8 Hz, 1H),
4.59 (dd, J = 9.6, 13.2 Hz, 1H), 5.39 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H). HPLC:
368

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
Chiralcel OD-H column, hexane:isopropanol (90:10), 1 mL/min, 267 nm, major enantiomer tr = 20.6 min,
minor enantiomer tr = 26.06 min, 52% ee, [α]2D5 = -0.9 (c 2.19, CH2 Cl2).
(R)-1-phenyl-2-nitroethanol (4h)
Yellow oil, 29% yield, 1H-NMR (CDCl3 , δ ppm), 3.08 (br, 1H), 4.49 (dd, J = 2.8, 13.2 Hz, 1H), 4.59
(dd, J = 9.6, 13.6 Hz, 1H), 5.43 (dd, J = 2.8, 9.6 Hz, 1H), 7.38 (m, 5H). HPLC: Chiralcel OD-H column,
hexane:isopropanol (90:10), 1 mL/min, 267 nm, major enantiomer tr = 14.1 min, minor enantiomer tr = 16.4
min, 51% ee, [α]2D5 = -25.8 (c 1.0, CH2 Cl2).
(R)1-(4-chlorophenyl)-2-nitroethanol (4i)
Colorless oil, 42% yield, 1 H-NMR (CDCl3 , δ ppm), 2.96 (br, 1H), 4.49 (dd, J = 9.2, 13.2 Hz, 1H), 4.57
(dd, J = 9.2, 13.6 Hz, 1H), 5.44 (dd, J = 2.8, 9.6 Hz, 1H), 7.33 (m, 4H). HPLC: Chiralcel OD-H column,
hexane:isopropanol (90:10), 1 mL/min, 267 nm, major enantiomer tr = 13.8 min, minor enantiomer tr = 17.4
min, 51% ee, [α]2D5 = -22.1 (c 1.45, CH2 Cl2).
(R)1-(2-methoxyphenyl)-2-nitroethanol (4j)
Yellow oil, 40% yield, 1 H-NMR (CDCl3 , δ ppm) 3.15 (d, J = 6 Hz, 1H), 3.88 (s, 3H), 4.57 (dd, J = 9.2,
13.2, 1H), 4.64 (dd, J = 3.2, 13.2 Hz, 1H), 5.65-5.61 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 7.01 (td, J = 0.8,
7.6 Hz, 1H), 7.33 (td, J = 0.8, 1.6 Hz, 1H), 7.44 (dd, J = 0.8, 7.2 Hz, 1H). HPLC: Chiralcel OD-H column,
hexane:isopropanol (90:10), 1 mL/min, 267 nm, major enantiomer tr = 11.3 min, minor enantiomer tr = 12.9
min, 53% ee, [α]2D5 = -26.4 (c 1.51, CH2 Cl2).
Results and discussion
Amino alcohols (1a-c) derived from the chiral amino acid L-tert-Leucine were obtained by addition of a Grignard
reagent to the methyl ester of the amino acid. These chiral amino alcohols were reacted with different aldehydes
to give Schiff base ligands (3a-k) in high yields. The ligands were appraised as catalysts for the Henry reaction
by carrying out reactions between 4-nitrobenzaldehyde and nitromethane in THF solvent in the presence of
Cu(OAc)2 .nH2 O. It was determined that the desired β-nitroalcohol was obtained in these reactions. However,
we were surprised to observe that for all our ligands the R enantiomer of the product β-nitroalcohol was
the major stereoisomer formed. By contrast, ligands B-D had all afforded the S enantiomer as the major
stereoisomer. Yields and observed enantiomeric excesses of the products are given in Table 1.
The experimental results (Table 1) showed that substitution on the phenol ring had a significant influence
on the enantioselectivity and the reaction yield. The best results were obtained when an alkoxy group such as
methoxy (Table 1, Entry 6) or benzyloxy (Table 1, Entry 5) was present in the 3-position of the phenol ring.
Surprisingly, replacing this alkoxy group with a hydroxyl group (Table 1, Entry 4) afforded a decrease in both
yield and enantiomeric excess. Introduction of a substituent at the 5-position of the aromatic ring also led to
369

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
surprising effects, for example ligand 3b, which contained a tert-butyl group in this position, afforded only a
very low enantiomeric excess (Table 1, Entry 2).
Table 1. Optimization of catalytic ligands (3a-k) effect on the asymmetric Henry reaction.
OH
CHO
NO2
2.5% mol Ligand 3a-k
Cu(OAc)2.nH2O
*
+
CH3NO2
THF, RT
O2N
O2N
Entry Ligand Time (h) Yieldb (%) eec (%) Configd
1
2
3a
3b
3c
3d
3e
3f
24
24
24
24
24
24
24
24
24
24
24
47
25
52
31
70
72
35
70
38
52
46
16
2
R
R
R
R
R
R
R
R
R
R
R
3
25
9
4
5
38
47
12
15
10
12
19
6
7
3g
3h
3i
8
9
10
11
3j
3k
a All reactions were performed with 0.5 mmol 4-Nitro-benzaldehyde, 2.5% mol ligand and Cu(OAc)2 .nH2 O, and 5 mmol
nitromethane in 1 mL of THF at room temperature.
b Isolated yields by column chromatography using 5:1 hexane:ethyl acetate.
c Determined by HPLC with OD-H column using hexane:isopropanol (90:10).
d Absolute configurations were determined by comparison of the values with the literature values. 7−19
After the selection of the catalyst, the effect of solvent was investigated (Table 2, Entries 1-12). It can be
seen that ethereal solvents such as THF, ether, and dioxane gave reasonable yields and enantiomeric excesses.
However, when alcohols were used as solvents disappointing enantiomeric excesses were obtained. The optimum
solvent was determined to be tert-butylmethylether (TBME). This result contrasts with previous studies where
alcoholic solvents16−18 or CH2 Cl127 were found to afford higher enantiomeric excesses. Subsequently, the
catalyst loadings were tested (Table 2, Entries 14-16) and 10 mol % was found to afford the best results. In
addition, to observe the effect of temperature on the process, one reaction was carried out at 0 ◦ C. Although
a slight increase in enantiomeric excess was obtained, the reaction took a longer time and gave a lower yield
(Table 2, Entry 13).
370

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
Table 2. The solvent effect on the asymmetric Henry reaction between nitromethane and 4-nitrobenzaldehdye in the
presence of 10% mol ligand 3f and Cu(OAc)2 .nH2 O.
OH
CHO
+
NO2
10% mol Ligand 3f
Cu(OAc)2.nH2O
*
CH3NO2
Solvent
O2N
O2N
Entry
1
Solvent
T (◦C) Time (day) Yieldb (%) eec (%) Config
THF
Ethanol
CH2Cl2
Et2O
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2
2
2
2
2
2
2
2
2
2
2
2
6
2
2
2
44
60
25
50
52
56
54
55
37
40
40
22
61
68
76
65
47
31
37
49
14
27
35
55
41
30
39
39
66
58
63
48
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
2
3
4
5
Methanol
Iso-propanol
Dioxane
TBME
6
7
8
9
EtOAc
10
11
12
13
14d
15e
16f
Hexane
CH3CN
Toluene
TBME
◦
0 C
TBME
rt
rt
rt
TBME
TBME
a Reactions were performed with 0.5 mmol 4-nitro-benzaldehyde, 10% mol ligand and Cu(OAc)2 .nH2 O, and 5 mmol
nitromethane in 1 mL of solvent.
b Isolated yields by the column chromatography using 5:1 hexane:ethyl acetate.
c Determined by HPLC with OD-H column using hexane:isopropanol (90:10).
d 5 mol % of ligand and Cu(OAc)2 .nH2 O were used.
e 10 mol % of ligand and Cu(OAc)2 .nH2 O were used.
f 1.25 mol % of ligand and Cu(OAc)2 .nH2 O were used.
Finally, using the optimized conditions, a variety of aromatic aldehydes were employed as substrates
(Table 3, Entries 1-10). Using these conditions, the expected products were obtained with moderate to
good enantiomeric excesses (48%-63%) and yields (18%-76%). These enantiomeric excesses and yields are
comparable to those obtained by Mao18 using ligand D and superior to those obtained by Punniyamurthy17
using ligand C. However, Wang,16 using ligand B, had obtained even better enantioselectivity. These results
suggest that it is important to have substituents at both carbons of the amino alcohol functionality and that
substituents containing aromatic groups may be the preferred options. Consistent with this suggestion, Ma and
371

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
coworkers14 very recently reported the preparation of a series of interesting ligands (E) (Figure 4) containing
a paracyclophane group attached to a tridentate ONO Schiff base functionality. When applied to the Henry
reaction in the presence of Cu(OAc)2 .nH2 O, good enantiomeric excesses of the desired β-nitroalcohol could
be obtained. In these cases, CH2 Cl2 was determined to be the optimum solvent, and, as in our results, the
R enantiomer was the major stereoisomer formed. However, enantiomeric excesses were found to be strongly
dependent on the nature of the R group present on the cyclophane group.
Table 3. Range of the aldehydes used in the Henry reactions in the presence of 10% mol ligand 3f and Cu(OAc)2 .nH2 O.
Entry Product T (◦C) Time (Day) Yield (%) ee (%) Config
1
2
4a
4b
4c
4d
4e
4f
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2
2
2
3
5
5
3
4
4
5
76
63
54
25
18
20
48
29
42
40
63
52
48
49
58
59
52
51
51
53
R
R
R
R
R
R
R
R
R
R
3
4
5
6
7
4g
4h
4i
8
9
10
4j
R
OH
N
HO
Figure 4. The structure of ligand E.
372

Tridentate ligands derived from L-tert-Leucine for the Cu(II)..., N. KORKMAZ, et al.
Conclusion
Schiff base ligands 3a-k were synthesized that contain a tert-butyl group and their effects on the asymmetric
Henry reaction as a catalyst were studied. Moderate to good enantiomeric excesses (up to 66%) of the products
were obtained.
Acknowledgements
¨
˙
The authors are grateful to The Scientific and Technological Research Council of Turkey (TUBITAK) for their
support (project number 107T778).
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374

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