Asymmetric Henry reaction catalyzed by Cu(I)-based chiral amino alcohol complex

Article abstract of DOI:10.3906/kim-1210-62

The Cu(I)-based complex prepared from (S)-2-(furan-2-yl-methylamino)-2- phenylethanol (5c) and CuCl was used as catalyst in enantioselective Henry reactions of arylaldehydes and nitromethane, which gave 89% ee and 95% yield at ambient temperature. The proposed catalytic cycle of an asymmetric Henry reaction was suggested. TUeBITAK.

Full text of DOI:10.3906/kim-1210-62

Turk J Chem
Turkish Journal of Chemistry
(2013) 37: 966 – 977
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1210-62
Research Article
Asymmetric Henry reaction catalyzed by Cu(I)-based chiral amino alcohol
complex
Tianhua SHEN, Quan QIN, Hang NI, Ting XIA, Xiaocong ZHOU, Funa CUI, Junqi LI,
Deqiang RAN, Qingbao SONG∗
The State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou, P. R. China
Received: 31.10.2012
•
Accepted: 11.06.2013
•
Published Online: 04.11.2013
•
Printed: 29.11.2013
Abstract: The Cu(I)-based complex prepared from (S)-2-(furan-2-yl-methylamino)-2-phenylethanol (5c) and CuCl was
used as catalyst in enantioselective Henry reactions of arylaldehydes and nitromethane, which gave 89% ee and 95%
yield at ambient temperature. The proposed catalytic cycle of an asymmetric Henry reaction was suggested.
Key words: Chiral amino alcohol, copper(I) salt, asymmetric catalysis, Henry reaction
1. Introduction
The Henry or nitroaldol reaction is one of the most powerful carbon–carbon bond forming reactions in organic
chemistry,1 and the CH-NO2 moiety in nitro alcohol adducts can be subjected to subsequent reactions to afford
other functionalities, for instance, ketone, aldehyde, carboxylic acid, and amino compounds,2 which are highly
valuable building blocks in asymmetric organic synthesis. Hence, the stereoselective Henry reaction has already
been applied in the synthesis of various compounds.
Since the first asymmetric Henry reaction was reported by Shibasaki in 1992,3 various versions of metal-
catalyzed asymmetric Henry reactions have been reported. Because of its cheap price, low toxicity, and excel-
lent chelating properties with ligands, copper has been widely used in organic synthesis. Copper can coordi-
nate with many ligands,4 such as bisoxazolines,5 trisoxazolines,5f boron-bridged bisoxazoline,6 thiaoline,5c,d
bisoxazolidine,7 amino alcohol,8 imino alcohols,9 aminopyridine,10 iminopyridine,11 bipiperidine,12 camphor
-imidazoline,13 imidazole derivatives,14 sparteine,15 oxabispidine,16 diamine,17 trianglamine,18 Schiff-base,19
N,N’-dioxide,20 tetrahydrosalen,21 cinchona alkaloid,22 and thiophene.23 Many of these copper-based com-
plexes catalyze the asymmetric Henry reaction with high yields and ee values.
Herein we describe the synthesis and applications of a series of copper(I) complexes prepared from (S)-
amino alcohol 4, 5, and CuCl; the addition of nitro alkanes to aldehyde gave ee up to 89%. The aldehydes are
compatible with this protocol, providing the corresponding nitroaldol products in high yields.
2. Experimental
2.1. General procedures
All solvents were dried by the standard method. Unless otherwise noted, commercially available reagents were
used without further purification. All reactions were monitored by TLC with Haiyang GF254 silica gel coated
∗Correspondence: qbsong@zjut.edu.cn
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plates. Column chromatography was carried out using 100–200 mesh silica gel. Liquid aldehydes were freshly
distilled before use.
Melting points were obtained with an X-4 micromelting point apparatus and are uncorrected. Optical
rotations were determined in a solution of CH2 Cl2 at 20 ◦ C by using an Autopol IV polarimeter. IR spectra
were recorded by a Veptor-22 FT-IR spectrometer. 1 H NMR and 13 C NMR spectra were obtained in CDCl3 on
a Bruker AVANCE III 500 MHz and 125 MHz spectrometers, respectively, using TMS as the internal reference.
J values were given in hertz. Mass spectra were carried out on a VARIAN1200 and measured by the EI method.
Chiral HPLC analyses were performed by using a SHIMADZU LC-20AT instrument equipped with a
SHIMADZU SPD-20A detector with chiral stationary phase column (Daicel Co. Chiralcel AD-H and OJ-H).
Retention times are given in minutes.
2.2. Preparation of ligands’ backbone
(S)-Phenylalanine methyl ester hydrochloride (1). SOCl2 (11 mL, 155 mmol) was added dropwise to
methanol (100 mL) in a 250-mL round-bottomed flask at –10 ◦ C. After stirring for 15 min, L-phenylalanine
(16.5 g, 100 mmol) was added. After being warmed up to ambient temperature and stirred for 3 h, the reaction
mixture was refluxed for 2 h. Then the reaction mixture was condensed under reduced pressure; the residue
was filtered and washed with ethanol to give compound 1. Yield: 85%. mp 156–158 ◦ C (lit.24 = 157–158 ◦ C).
(S)-2-Amino-1,1,3-triphenylpropan-1-ol (2). (S)-Phenylalanine methyl ester hydrochloride 2.16 g
(10 mmol) was added portionwise to freshly prepared Grignard reagent of PhMgBr (80 mmol) in diethyl ether
under an argon atmosphere at 0 ◦ C. Then the mixture was stirred at ambient temperature overnight, and a
cold saturated NH4 Cl was added into it under vigorous stirring. The mixture was extracted with ethyl acetate
(50 mL × 3). The combined organic layer was washed with brine and dried with anhydrous Na2 SO4 , and
then concentrated in a vacuum. This residue was recrystallized with diethyl ether and gave compound 2 as a
colorless crystal. Yield: 65.3%; mp 144–145 ◦ C (lit.25 = 154–155 ◦ C).
(S)-2-Phenylglycinol (3). A 250-mL 3-neck round-bottomed flask was fitted with a magnetic stir bar,
a reflux condenser, and an addition funnel. The flask was charged with 3.31 g (91 mmol) of sodium borohydride
and 100 mL of THF (predried over sodium). L-phenylglycine (5.74 g, 38 mmol) was added in one portion. The
remaining neck was sealed with a septum and an argon line attached, and the flask was cooled to 0 ◦ C in an ice
bath. A solution of 9.65 g (38 mmol) of iodine dissolved in 25 mL of THF was poured into the addition funnel
and added dropwise over 30 min, resulting in vigorous evolution of hydrogen. After addition, the reaction was
complete and gas evolution had ceased, and the flask was heated to reflux for 18 h and then cooled to ambient
temperature, and methanol was added cautiously until the mixture became clear. After stirring for 30 min, the
solvent was removed by rotary evaporation, leaving a white paste, which was dissolved by adding 150 mL of
20% aqueous NaOH. The solution was stirred for 4 h and extracted with CH2 Cl2 (50 mL × 3). The organic
phase was dried with anhydrous Na2 SO4 and concentrated in a vacuum. Then the white crude product was
recrystallized in toluene to afford 3 as a colorless crystal. Yield: 65.3%; mp 72–73 ◦ C (lit.26 = 69–71 ◦ C).
2.3. General procedure of the preparation for ligands 4a–4e
To a solution of an aldehyde (3.0 mmol) and 2 (0.91 g, 3.0 mmol) in 10 mL of CH2 Cl2 was added anhydrous
MgSO4 (1.0 g), and the mixture was stirred at ambient temperature until the reaction was complete (monitored
by TLC). Then the reaction mixture was filtered, and the filtrate was distilled under reduced pressure. Then
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the Schiff base was obtained and dissolved in MeOH (10 mL) and THF (10 mL). After cooling to 0 ◦ C, NaBH4
(0.23 g, 6.0 mmol) was added in portions; then the mixture was stirred at ambient temperature until the reaction
was complete. After the removal of the solvent, aqueous hydrochloric acid (1 N) was added until pH 8–9. Then
the mixture was extracted with CH2 Cl2 (20 mL × 3), and the organic phase washed with brine, dried with
anhydrous Na2 SO4 , and evaporated to give the crude product. Then the residue was purified on silica gel
column chromatography.
(S)-2-(3,4-Dimethoxybenzylamino)-1,1,3-triphenylpropan-1-ol (4a). 78% yield; mp 129–130
◦ C; [α]2D0 = –313 (c = 0.010, CH2 Cl2), 1 H NMR (δ, ppm): 7.80–7.13 (15H, m, Ph-H), 6.61 (1H, d, J = 8.5
Hz, Ar-H), 6.17 (1H, dd, J = 8.0, 1.5 Hz, Ar-H), 6.11 (1H, d, J = 1.5 Hz, Ar-H), 3.97 (1H, dd, J = 11.0,
3.0 Hz, C*HN), 3.81 (3H, s, OCH3), 3.69 (3H, s, OCH3), 2.97–2.88 (3H, m, J = 14.5, 11.0, 3.0 Hz, CH2 N,
PhCH2), 2.36 (1H, dd, J = 14.5, 10.5 Hz, PhCH2); 13 C NMR (δ, ppm): 148.62, 147.89, 144.62, 139.34,
132.28, 129.05, 128.56, 128.20, 128.09, 126.62, 126.47, 126.41, 126.05, 125.62, 120.08, 111.28, 110.71, 78.17,
77.03, 76.78, 65.50, 58.36, 55.81, 55.63, 53.63, 37.58; IR (KBr, cm−1): 3451.2, 3322.6, 3003.6, 2907.1, 2853.5,
1581.0, 1494.0, 1370.2, 1158.3, 797.7, 768.4, 701.6; MS (m/z, %): 454 ((M + 1)+ , 12.6), 362 (5.1), 270 (99.9),
183 (18.2), 151 (99.3), 105 (98.2), 91 (45.7), 77 (88.6).
(S)-2-((4-Bromothiophen-2-yl)methylamino)-1,1,3-triphenylpropan-1-ol (4b). 85% yield; mp
200–201 ◦ C; [α]2D0 = –150 (c = 0.023, CH2 Cl2); 1 H NMR (δ, ppm): 7.44–7.11 (15H, m, Ph-H), 7.00 (1H,
d, J = 1.0 Hz, thiophene-H), 6.89 (1H, d, J = 1.4 Hz, thiophene-H), 3.12–3.00 (2H, m, CH2 N), 2.87–2.79
(2H, m, PhCH2), 2.75 (1H, dd, J = 3.5, 13.8 Hz, C*HN); 13 C NMR (δ, ppm): 145.66, 142.76, 140.36, 138.22,
130.88, 130.54, 129.47, 129.35, 128.93, 128.21, 126.34, 126.12, 121.44, 89.91, 77.82, 73.65, 47.45, 34.51; IR (KBr,
cm−1): 3492.1, 2961.0, 2893.0, 1600.8, 1491.5, 1448.5, 1365.4, 1156.9, 811.4, 750.9, 699.0, 579.8; MS (m/z, %):
478 ((M + 1)+ , 2.5), 386 (2.4), 296 (30.8), 183 (99.9), 176 (17.2), 105 (95.9), 91 (97.4), 77 (99.9).
(S)-2-(Furan-2-ylmethylamino)-1,1,3-triphenylpropan-1-ol (4c). 60% yield; mp 80–81 ◦ C; [α]D20
= –52.3 (c = 0.022, CH2 Cl2); 1 H NMR (δ, ppm): 7.73–7.02 (16H, m, Ph-H, furan-H), 6.14 (1H, dd, J =
2.5, 2.0 Hz, furan-H), 5.69 (1H, d, J = 3.0 Hz, furan-H), 4.80 (1H, br, NH), 3.97 (1H, dd, J = 10.5, 2.8 Hz,
C*HN), 3.13 (1H, d, J = 14.5 Hz, CH2 N), 2.92–2.86 (2H, m, CH2 NH, PhCH2), 2.35 (1H, dd, J = 14.5, 10.5
Hz, PhCH2), 1.62 (1H, br, OH); 13 C NMR (δ, ppm): 152.93, 147.47, 145.05, 141.74, 139.12, 128.90, 128.58,
128.20, 126.73, 126.46, 126.25, 126.00, 125.62, 109.62, 106.96, 78.05, 77.29, 77.03, 76.78, 63.85, 44.81, 37.48; IR
(KBr, cm−1): 3340.2, 3022.3, 2922.5, 1599.6, 1492.5, 1449.1, 1366.8, 1212.7, 1147.5, 802.0, 740.8, 699.2; MS
(m/z, %): 384 ((M + 1)+ , 3.1), 200 (99.9), 183 (13.6), 105 (99.0), 91 (75.2), 77 (97.3).
(S)-2-((1H -pyrrol-2-yl)methyleneamino)-1,1,3-triphenylpropan-1-ol (4d). The title compound
was prepared according to the general procedure without the reduction with NaBH4 and purified by recrystal-
lization from ethanol. 65% yield; mp 196–197 ◦ C; [α]D20 = –178 (c = 0.015, CH2 Cl2); 1 H NMR (δ, ppm):
7.68–6.94 (16H, m, Ph-H, CH = N), 6.64 (1H, s, pyrrol-H), 6.16 (1H, d, J = 2.5 Hz, pyrrol-H), 6.07 (1H, dd, J
= 3.5, 3.0 Hz, pyrrol-H), 4.36 (1H, dd, J = 13.5, 6.0 Hz, C*HN), 2.84 (2H, d, J = 6.0 Hz, PhCH2); 13 C NMR
(δ, ppm): 152.76, 139.50, 129.98, 128.41, 128.15, 126.64, 126.37, 126.24, 126.06, 125.59, 114.69, 114.67, 109.57,
79.64, 77.38, 77.29, 77.03, 76.78, 37.17; IR (KBr, cm−1): 3411.4, 3025.1, 2934.1, 1636.2, 1602.0, 1493.2, 1449.9,
1366.7, 1176.0, 808.9, 750.5, 700.8; MS (m/z, %): 381 ((M + 1)+ , 3.4), 197 (99.9), 183 (49.0), 105 (99.1), 91
(77.5), 77 (97.9).
(S)-2-(Naphthalen-2-ylmethylamino)-1,1,3-triphenylpropan-1-ol (4e). 85% yield; mp 196–197
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◦ C; [α]2D0 = –61.0 (c = 0.020, CH2 Cl2); 1 H NMR (δ, ppm): 7.77–6.86 (22H, m, Ar-H), 4.87 (1H, br, NH),
3.98 (1H, dd, J = 11.0, 3.0 Hz, C*HN), 3.12 (1H, d, J = 13.0 Hz, CH2 N), 3.22 (1H, d, J = 13.0 Hz, CH2 N),
2.96 (1H, dd, J = 14.5, 2.8 Hz, PhCH2), 2.38 (1H, dd, J = 14.5, 11.0 Hz, PhCH2), 1.54 (1H, br, OH); 13 C
NMR (δ, ppm): 147.65, 145.06, 139.39, 137.02, 133.14, 132.49, 129.15, 128.72, 128.23, 127.83, 127.67, 127.53,
126.53, 126.47, 126.35, 126.07, 125.84, 125.64, 125.58, 78.17, 77.30, 77.05, 77.03, 76.80, 65.42, 53.60, 37.73; IR
(KBr, cm−1): 3408.7, 3023.5, 2958.2, 1600.2, 1493.8, 1447.3, 1377.7, 1174.1, 861.5, 790.6, 697.9; MS (m/z, %):
444 ((M + 1)+ , 2.2), 260 (66.6), 183 (15.1), 105 (99.9), 91 (56.9), 77 (98.3).
2.4. General procedure of the preparation for ligands 5a–5e
To a solution of aldehyde 3.0 mmol and 3 (0.411 g, 3.0 mmol) in 10 mL of CH2 Cl2 was added anhydrous
MgSO4 (1.0 g), and the mixture was stirred at ambient temperature until the reaction completed (monitored
by TLC). After the solid material was removed by filtration the solvent was distilled under reduced pressure.
Then the Schiff base was obtained and dissolved in MeOH (10 mL) and THF (10 mL). After cooling to 0 ◦ C,
NaBH4 (0.23 g, 6.0 mmol) was added in portions; then the mixture was stirred at room temperature until the
reaction was over (monitored by TLC). After the removal of the solvent, aqueous hydrochloric acid (1 N) was
added until pH 8–9. Then the resulting mixture was extracted with CH2 Cl2 (20 mL × 3), and the organic
phase was washed with brine, dried with anhydrous Na2 SO4 , and evaporated to give the crude product. Then
the residue was purified on silica gel column chromatography. Amino alcohols 5a27 , 5c28 , 5d29 , and 5e30 are
known compounds.
(S)-2-(3,4-Dimethoxybenzylamino)-2-phenylethanol (5a). 79% yield; [α]2D0 = + 58.1 (c = 0.015,
CH2 Cl2); 1 H NMR (δ, ppm): 7.38–7.30 (5H, m, Ph-H), 6.82–6.78 (3H, m, Ph-H), 3.85 (3H, s, OCH3), 3.84
(3H, s, OCH3), 3.80 (1H, dd, J = 9.0, 4.2 Hz, C*HN), 3.69 (1H, d, J = 11.0 Hz, CH2 N), 3.68 (1H, d, J = 12.5
Hz, CH2 O), 3.57 (1H, d, J = 10.5 Hz, CH2 N), 3.54 (1H, d, J = 13.0 Hz, CH2 O), 2.51 (2H, br, NH, OH); IR
(KBr, cm−1): 3406.3, 3001.9, 2935.0, 2834.8, 1582.3, 1515.9, 1453.8, 1344.9, 1156.6, 854.5, 808.0, 762.6, 703.0.
MS (m/z, %): 196 (74.5), 104 (24.5), 91 (99.9).
(S)-2-((4-Bromothiophen-2-yl)methylamino)-2-phenylethanol (5b). 80% yield; [α]2D0 = + 68.6
(c = 0.010, CH2 Cl2); 1 H NMR (δ, ppm): 7.39–7.28 (5H, m, Ph-H), 7.10 (1H, d, J = 1.5 Hz, thiophene-H),
6.77 (1H, d, J = 1.0 Hz, thiophene-H), 3.88 (1H, dd, J = 14.5, 0.5 Hz, CH2 N), 3.83 (1H, dd, J = 9.5, 4.2 Hz,
C*HN), 3.76 (1H, dd, J = 14.5, 0.5 Hz, CH2 N), 3.70 (1H, dd, J = 11.0, 4.5 Hz, CH2 O), 3.57 (1H, dd, J =
11.0, 4.5 Hz, CH2 O), 2.81 (2H, br, NH, OH); IR (KBr, cm−1): 3417.9, 3027.8, 2926.1, 2869.4, 1635.1, 1528.4,
1453.6, 1345.8, 1153.2, 857.4, 758.7, 701.4, 583.9; MS (m/z, %): 312 ((M + 1)+ , 0.9), 280 (61.2), 175 (99.9),
104 (12.6).
(S)-2-(Furan-2-ylmethylamino)-2-phenylethanol (5c). 60% yield; mp 69–70 ◦ C; [α]D20 = + 98.8
(c = 0.015, CH2 Cl2); 1 H NMR (δ, ppm): 7.40–7.30 (5H, m, Ph-H), 7.29 (1H, d, J = 2.0 Hz, furan-H), 6.29
(1H, dd, J = 3.0, 2.0 Hz, furan-H), 6.11 (1H, d, J = 3.5 Hz, furan-H), 3.79 (1H, dd, J = 8.5, 4.0 Hz, C*HN),
3.74 (1H, d, J = 14.5 Hz, CH2 N), 3.70 (1H, dd, J = 11.0, 4.5 Hz, CH2 O), 3.60 (1H, d, J = 14.0 Hz, CH2 N),
3.58 (1H, dd, J = 11.0, 8.5 Hz, CH2 O), 2.37 (2H, br, NH, OH); IR (KBr, cm−1): 3265.6, 3031.0, 2919.1,
2864.1, 1602.2, 1493.7, 1454.0, 1337.4, 1196.9, 1145.6, 807.7, 763.2, 703.8; MS (m/z, %): 218 ((M + 1)+ , 9.8),
186 (99.9), 81 (99.8), 77 (96.6).
(S)-2-((1H -pyrrol-2-yl)methyleneamino)-2-phenylethanol (5d). This compound was prepared
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according to the general procedure without the reduction with NaBH4 and purified by recrystallization from
ethanol. 60% yield; mp 196–197 ◦ C; [α]D20 = + 156 (c = 0.018, CH2 Cl2); IR (KBr, cm−1): 3331.3, 3061.3,
2857.7, 1640.6, 1489.0, 1448.5, 1366.7, 1180.1, 813.2, 736.5, 700.8; MS (m/z, %): 214 (M+ , 21.0), 183 (99.9),
79 (37.3), 77 (48.9).
(S)-2-(Naphthalen-2-ylmethylamino)-2-phenylethanol (5e). 75% yield; [α]2D0 = + 43.6 (c =
0.015, CH2 Cl2); 1 H NMR (δ, ppm): 7.82–7.28 (12H, m, Ar-H), 3.89 (1H, d, J = 13.5 Hz, CH2 N), 3.83 (1H,
dd, J = 8.5, 4.2 Hz, C*HN), 3.73 (1H, d, J = 12.5 Hz, CH2 N), 3.70 (1H, dd, J = 10.8, 4.0 Hz, CH2 O), 3.57
(1H, dd, J = 11.0, 8.5 Hz, CH2 O), 2.26 (2H, br, NH, OH); IR (KBr, cm−1): 3284.7, 3028.4, 2926.0, 2852.9,
1944.8, 1600.7, 1491.8, 1452.9, 1366.3, 1175.0, 870.4, 825.9, 700.1; MS (m/z, %): 278 ((M + 1)+ , 1.2), 246
(99.9), 105 (93.0), 81 (99.8), 77 (29.6).
2.5. General procedure of the asymmetric Henry reaction
The chiral ligand (0.03 mmol) and CuCl (0.03 mmol) were put in a 10-mL round-bottomed flask. Ethanol (1.5
mL) was added and the mixture was stirred for 1 h at ambient temperature (18 ◦ C). Usually a color change
from colorless to greenish was observed during this time. Subsequently, the desired aldehyde (0.3 mmol) was
added, followed by slow addition of 0.16 mL (3 mmol) of nitromethane via syringe. The reaction was monitored
by TLC until completed. The volatile components were removed in vacuo and the crude product was purified by
preparative TLC with petroleum ether/ethyl acetate to afford the desired β -nitroalcohol. Enantiomeric excess
was determined by using HPLC with Chiracel OJ-H or Chiralpak AD-H chiral columns.
2-Nitro-1-phenylethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH = 95:5; flow
rate: 0.5 mL/min; λ = 230 nm; tminor = 36.46 min, tmajor = 37.66 min; 55% ee. Corresponding racemic
compound’s retention time: τ1 = 34.59 min, τ2 = 35.73 min.
2-Nitro-1-(4-Nitrophenyl)ethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH =
65:35; flow rate: 1.0 mL/min; λ = 254 nm; tmajor = 10.23 min, tminor = 13.04 min; 89% ee. Corresponding
racemic compound’s retention time: τ1 = 10.08 min, τ2 = 12.73 min.
2-Nitro-1-(3-Nitrophenyl)ethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH =
68:32; flow rate: 0.7 mL/min; λ = 254 nm; tminor = 7.91 min, tmajor = 8.68 min; 76% ee. Corresponding
racemic compound’s retention time: τ1 = 7.89 min, τ2 = 8.67 min.
2-Nitro-1-(2-Nitrophenyl)ethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH =
70:30; flow rate: 0.5 mL/min; λ = 254 nm; tminor = 11.70 min, tmajor = 12.25 min; 88% ee. Corresponding
racemic compound’s retention time: τ1 = 11.81 min, τ2 = 12.34 min.
2-Nitro-1-(4-Chlorophenyl)ethanol. Chiral HPLC (Daicel Chiralpak Chiralcel OJ-H), n-hexane:
i-PrOH = 85:15; flow rate: 1.0 mL/min; λ = 220 nm; tmajor = 6.08 min, tminor = 12.91 min; 86% ee.
Corresponding racemic compound’s retention time: τ1 = 5.49 min, τ2 = 12.26 min.
2-Nitro-1-(3-Chlorophenyl)ethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH =
85:15; flow rate: 0.5 mL/min; λ = 215 nm; tminor = 13.71 min, tmajor = 14.89 min; 41% ee. Corresponding
racemic compound’s retention time: τ1 = 13.19 min, τ2 = 14.28 min.
2-Nitro-1-(2-Chlorophenyl)ethanol. Chiral HPLC (Daicel Chiralpak Chiralcel OJ-H), n-hexane:
i-PrOH = 95:5; flow rate: 0.8 mL/min; λ = 215 nm; tmajor = 27.11 min, tminor = 28.04 min; 36% ee.
Corresponding racemic compound’s retention time: τ1 = 26.53 min, τ2 = 27.49 min.
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1-(2,5-Dimethoxyphenyl)-2-nitroethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-
PrOH = 90:10; flow rate: 0.7 mL/min; λ = 215 nm; tminor = 24.72 min, tmajor = 25.79 min; 71% ee.
Corresponding racemic compound’s retention time: τ1 = 24.33 min, τ2 = 25.33 min.
1-(Naphthalen-2-yl)-2-nirtoethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH =
85:15; flow rate: 0.5 mL/min; λ = 230 nm; tminor = 31.96 min, tminor = 33.99 min; 55% ee. Corresponding
racemic compound’s retention time: τ1 = 31.45 min, τ2 = 33.12 min.
1-(Furan-2-yl)-2-nitroethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-PrOH = 85:15;
flow rate: 1.0 mL/min; λ = 225 nm; tmajor = 15.62 min, tminor = 16.35 min; 58% ee. Corresponding racemic
compound’s retention time: τ1 = 16.02 min, τ2 = 16.72 min.
1-(4-Bromothiophen-2-yl)-2-nitroethanol. Chiral HPLC (Daicel Chiralpak AD-H), n-hexane: i-
PrOH = 95:5; flow rate: 1.0 mL/min; λmax = 230 nm; tminor = 17.01 min, tmajor = 19.51 min; 86% ee.
Corresponding racemic compound’s retention time: τ1 = 17.19 min, τ2 = 19.83 min.
2.6. General procedure for preparation of the racemic Henry reaction products
The aldehyde (0.3 mmol) was added to a 10-mL round-bottomed flask. Then ethanol (1.5 mL) was added at
ambient temperature (18 ◦ C). Subsequently, nitromethane (0.16 mL, 3 mmol) was injected via syringe. The
reaction was monitored by TLC until complete conversion was achieved (about 8 h). The volatile components
were removed in vacuo and the crude product was purified by preparative TLC with petroleum ether/ethyl
Ph
NH
5c
OH
O
CH3NO2
CuCl
Ph
Ph
NH
OH
NH
OH
CH3
N
Cu
Cl
O
Cu
O
Cl
O
O
I
II
OH
Ph
NO2
Product
R
NH
OH
RCHO
Cu
O
H
O
O
HCl
HCl
N
R
O
III
Figure. Proposed catalytic cycle for the enantioselective Henry reaction.
971

SHEN et al./Turk J Chem
acetate, which gave the racemic β -nitroalcohol. Retention time was determined by using HPLC with Chiracel
OJ-H or Chiralpak AD-H chiral columns.
3. Results and discussion
The L-phenylalaninol ligands 4a–e were synthesized from L-phenylalanine as a starting material through 4
simple steps and the L-2-phenylglycinol ligands 5a-e were synthesized from L-phenylglycine through 3 steps
(Scheme).
With these series of amino alcohols in hand, we began to evaluate these ligands for the enantioselective
Henry reaction. During our initial experiments, ligands 4a–e were used in the additive reaction of nitromethane
top-nitrobenzaldehyde at ambient temperature in methanol (Table 1). This type of ligand showed poor catalytic
activity and enantio- selectivity in this reaction (Table 1, entries 1–5). It is possible that the phenyl rings on
the α-carbon atom of the hydroxyl group gave significant steric hindrance, and so the substrate was too hard
to combine with the copper complex. Then we changed the backbone of the ligand. The L-2-phenylglycinol
type ligand 5b showed the best enantioselectivity (Table 1, entry 7). Although the enantiomeric excess was
enhanced to 44%, the yield was still moderate. When triethylamine was added, the reaction was complete in
12 h with good yields, but the products were almost racemic (Table 1, entries 11 and 12).
Table 1. The model enantioselective Henry reactions of p-nitrobenzaldehyde with nitromethane using different ligands.
OH
.
Cu(OAc)2 H2O (10 mol%)
Ligand (10 mol%)
CHO
NO2
CH3NO2
+
CH3OH, rt
O2N
O2N
[b]
[c]
Entry[a] Ligand t (h) Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5b
5c
48
48
48
48
48
48
48
48
48
48
12
12
28
30
35
20
33
65
60
70
40
80
90
93
<5
<5
15
<5
<5
30
44
37
7
9
10
11
12
24
<5
<5
[a] Reactions were performed on a 0.3 mmol scale of aldehyde and 0.16 mL (3 mmol) of nitromethane. [b] Chromatogram
yield. [c] Enantiomeric excesses were determined by HPLC using a Chiral AD-H column. [d] Et3 N of 10 mol % was
used as the additive.
From Table 2, several kinds of copper salt as Lewis acid were selected and evaluated for the enantioselective
Henry reaction at ambient temperature. CuCl was found to be the best copper salt for this reaction, with high
enantiomeric excess and moderate yield (Table 2, entries 3 and 4). CuBr showed the best enantiomeric excess,
but with low yield (Table 2, entry 8). A similar moderate yield was obtained by using CuI as Lewis acid, but
the products were almost racemic (Table 2, entries 9 and 10).
972

SHEN et al./Turk J Chem
Table 2. Effect of Lewis acid on the enantioselectivity.
OH
Lewis acid (10 mol%)
Ligand (10 mol%)
CHO
NO2
+
CH3NO2
CH3OH, rt, 48h
O2N
O2N
[a]
[b]
[c]
Entry
1
2
3
4
5
6
7
8
Ligand Lewis acid
Yield (%)
Ee (%)
44
37
69
74
39
41
69
77
5b
5c
5b
5c
5b
5c
5b
5c
5b
5c
Cu(OAc)2·H2O 65
Cu(OAc)2·H2O 70
CuCl
CuCl
CuCl2·2H2O
CuCl2·2H2O
CuBr
CuBr
CuI
CuI
83
80
20
20
30
35
77
86
9
10
<5
<5
[a] Reactions were performed on a 0.3 mmol scale of aldehyde and 0.16 mL (3 mmol) of nitromethane. [b] Chromatogram
yield. [c] Enantiomeric excesses were determined by HPLC using a Chiral AD-H column.
As shown in Table 3, it is clear that protic alcoholic solvents were superior to aprotic solvents (entries
1 and 2). The enantioselectivity was enhanced to 89% when using ethanol as the solvent (entry 2), and the
reaction rate became fast (entry 2). Coordinative solvents like alcohols might coordinate with copper ion, which
would enhance the enantioselectivity9 (entries 3, 4, and 6).
Table 3. Effect of solvent on the enantioselective Henry reaction.
OH
CuCl (10 mol%)
5c (10 mol%)
CHO
NO2
+
CH3NO2
solvent, rt
O2N
O2N
[a]
[b]
[c]
Entry
Solvent
MeOH
EtOH
CH2Cl2
PhMe
t (h) Yield (%)
Ee (%)
74
89
63
55
1
2
3
4
5
6
24
18
48
48
80
95
30
15
17
35
CH3NO2 48
THF 48
55
56
[a] Reactions were performed on a 0.3 mmol scale of aldehyde and 0.16 mL (3 mmol) of nitromethane. [b] Chromatogram
yield. [c] Enantiomeric excesses were determined by HPLC using a Chiral AD-H column.
Reaction temperature was the last optimized factor of the enantioselective Henry reaction (Table 4). At
–20 ◦ C, no corresponding product was checked by TLC (Table 4, entry 1). Then we conducted the reaction
under warm temperature, and both the yields and enantioselectivity were improved (Table 4, entries 2–4).
When the temperature was increased to 35 ◦ C, the reaction was faster than that at 18 ◦ C, but the ee value of
the product dropped (Table 4, entry 4).
973

SHEN et al./Turk J Chem
Table 4. Effect of temperature on the enantioselective Henry reaction.
OH
CuCl (10 mol%)
5c (10 mol%)
CHO
NO2
CH3NO2
+
C2H5OH,T
O2N
O2N
[a]
[b]
[c]
Entry
T (◦C) t (h) Yield (%)
Ee (%)
nd
90
89
83
1
2
3
4
–20
0
24
24
24
6
–
88
97
98
18
35
[a] Reactions were performed on a 0.3 mmol scale of aldehyde and 0.16 mL (3 mmol) of nitromethane. [b] Chromatogram
yield. [c] Enantiomeric excesses were determined by HPLC using a Chiral AD-H column.
Under optimal condition, several arylaldehydes were found to be suitable substrates (Table 5).
A
variety of aromatic, heteroaromatic aldehydes provided nitroalcohol products with good yields (up to 95%)
and good enantiomeric excesses in the range of 36% to 89%. It might be noted that the electronic character
of the substituent as well as its steric hindrance had rather slight influence on the enantioselectivities. The
enantioselectivities of the chiral products with para-substituents had a significant increase compared with ortho-
and meta-substituents (Table 5, entries 2–7), and these results correlated with the increased electrophilicity of
the substrates. Heteroaromatic aldehydes also gave nitroaldol products with good ee values (Table 5, entries 10
and 11).
Table 5. Scope of aldehydes in the enantioselective Henry reaction with nitromethane.
CuCl (10 mol%)
5c (10 mol%)
OH
O
NO2
CH3NO2
+
C2H5OH, rt
R
R
H
[a]
[b]
[c]
Entry
1
2
3
4
5
6
7
8
Aldehydes
Benzaldehyde
t (h) Yield (%)
Ee (%)
120
18
35
95
75
90
50
35
30
45
69
30
75
55
89
76
88
86
41
36
71
55
58
86
4-Nitrobenzaldehyde
3-Nitrobenzaldehyde
2-Nitrobenzaldehyde
4-Chlorobenzaldehyde
3-Chlorobenzaldehyde
2-Chlorobenzaldehyde
2,5-Dimethoxylbenzaldehyde
2-Naphthyl-aldehyde
Furan-2-carbaldehyde
48
30
120
120
120
96
9
10
11
48
120
4-Bromothiophene-2-carbaldehyde 41
[a] Reactions were performed on a 0.3 mmol scale of aldehyde and 0.16 mL (3 mmol) of nitromethane. [b] Chromatogram
yield. [c] Enantiomeric excesses were determined by HPLC using a Chiral AD-H or a Chiral OJ-H column.
Based on the previous results and relevant mechanism suggested by Evans,5e the proposed catalytic
cycle is shown in the Figure. The complex I was formed by the reaction from ligand 5c and CuCl. Due to
974

SHEN et al./Turk J Chem
the strong coordination ability of the nitro group to the center metal, nitromethane was activated through a
possible complex II. Then the aldehyde bonded to the copper ion to form the transition state III, and the
nitromethane was deprotonated to generate the active nucleophile simultaneously. Eventually, the product was
obtained through the attack of nucleophile.
Ph
Ph
CH3OH
SOCl2
PhMgBr
Et2O
COOH
NH2
COOMe
NH2
Ph
Ph
Ph
OH
NH2
2
¡¤HCl
1
R1CHO
Ph
Ph
Ph
Ph
NaBH4
Ph
OH
Ph
OH
HN
N
R1
R1
4a, b, c, e
4d
Ph
Ph
COOH
NH2
Ph
Ph
R1CHO
NaBH4
I2, THF
OH
NaBH4
OH
OH
R1
N
NH2
3
HN
R1
5d
5a, b, c, e
Br
MeO
MeO
R1=
N
H
O
S
4a, 5a
4e, 5e
4b, 5b
4c, 5c
4d, 5d
Scheme. Preparation of chiral amino alcohol type ligands 4 and 5.
4. Conclusion
The results of the experiment showed that the Cu(I)-based complex was prepared from (S)-2-(furan-2-yl-
methylamino)-2-phenylethanol (5c) with CuCl used as catalyst in the enantioselective Henry reaction of ary-
laldehydes and nitromethane with up to 89% ee values and 95% yield at ambient temperature. Under optimal
conditions, several arylaldehydes were found to be suitable substrates. The proposed catalytic cycle of the
asymmetric Henry reaction was suggested. Further studies about amino alcohols on asymmetric synthesis are
currently being undertaken by our group.
Acknowledgments
This work was financially supported by the National Science Foundation of Zhejiang Province (LY12B02016)
and the State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of
Technology (People’s Republic of China).
975

SHEN et al./Turk J Chem
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