Synthesis of N,O-type inherently chiral calix[4]arenes substituted on the lower rim and their organocatalysis properties

Article abstract of DOI:10.21577/0103-5053.20160307

This work presented the first study of organocatalytic behaviors of inherently chiral calix[4] arenes substituted at the lower rim. A pair of N,O-type enantiomers based on inherently chiral calix[4]arenes substituted at the lower rim were readily synthesi

Full text of DOI:10.21577/0103-5053.20160307

http://dx.doi.org/10.21577/0103-5053.20160307
J. Braz. Chem. Soc., Vol. 28, No. 8, 1363-1370, 2017.
Printed in Brazil - ©2017 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
Synthesis of N,O-Type Inherently Chiral Calix[4]arenes Substituted on the Lower
Rim and their Organocatalysis Properties
Ming-Liang Chang, Yong He, Jing Zhou* and Shao-Yong Li*
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics),
School of Pharmacy, Tianjin Medical University, 300070 Tianjin, China
This work presented the first study of organocatalytic behaviors of inherently chiral calix[4]
arenes substituted at the lower rim. A pair of N,O-type enantiomers based on inherently chiral
calix[4]arenes substituted at the lower rim were readily synthesized and applied to catalyze Henry
reaction between aromatic aldehydes and nitromethane. Their organocatalytic reaction can afford
the desired products in excellent yields (up to 99%) but poor enantioselectivities (up to 7.5% ee).
Keywords: inherently chiral, calix[4]arene, asymmetric catalysis, Henry reaction
Introduction
as acid-base bifunctional organocatalysts through H-bond
interactions with the acceptor and donor components
of the reactions through the quinuclidine nitrogen and
the aromatic hydroxyl, respectively.10,15,16 Therefore, we
attempted to synthesize chiral N,O-type organocatalysts
based on inherently chiral calix[4]arenes substituted at the
lower rim, and selected Henry reaction between aromatic
aldehydes and nitromethane as a model reaction to explore
their organocatalytic abilities.
Inherently chiral calixarenes as a novel type of chiral
macrocyclic compounds have been intensively studied
in the past three decades. To mimic enzymatic catalysis
process and develop efficient chiral catalysts, a variety
of inherently chiral calix[4]arenes substituted at the meta
position and the upper rim have been applied as chiral
organocatalysts in aldol reaction,1 addition of diethylzinc
to benzaldehyde,2 Michael addition3-7 and alkylation of a
glycine derivative.7 And the highest ee in these catalytic
reactions is up to 31%.6 However, until now inherently
chiral calix[4]arenes substituted at the lower rim have
not been applied in asymmetric organocatalysis although
they have been frequently prepared and applied in chiral
recognition.8 To systematically study the application of
inherently chiral calixarenes, it is necessary to explore
the organocatalytic behaviors of inherently chiral calix[4]
arenes substituted at the lower rim.
Henry reactions are one of the most useful and widely
employed methods for carbon-carbon bond formation in
organic chemistry. The resulting nitro alcohol (nitroaldol)
products can be transformed into a number of nitrogen and
oxygen-containing derivatives such as 1,2-amino alcohols,
amino sugars, nitro ketones, nitro alkenes, ketones, and
other important compounds.9-14 It was reported that chiral
N,O-type cupreidine derivatives can perform outstanding
catalytical activities for Henry reaction. Mechanistic
studies on their catalytic behaviors indicated they serve
Experimental
General experimental procedures
All reactions were conducted under atmosphere
without special drying.All chemicals were purchased from
commercial sources and used without further purification.
Melting points were measured on RY-1G melting point
apparatus. Nuclear magnetic resonance (NMR) spectra
were performed on Bruker Avance 400 (1H: 400 MHz,
13C: 101 MHz). CDCl3 (d 7.26 ppm), DMSO-d6 (d 2.50,
3.33 ppm) or TMS (d 0.00 ppm) was used as an internal
1
standard for H NMR spectra, CDCl3 (d 77.00 ppm),
DMSO-d6 (d 39.58 ppm) or TMS (d 0.00 ppm) was used
as an internal standard for 13C NMR spectra. The following
abbreviations are used to indicate the multiplicity in NMR
spectra: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, J indicates the NMR coupling constant
measured in Hertz. The courses of the reactions were
monitored by thin layer chromatography (TLC) using
TLC aluminium sheets with silica gel 60 GF254. The
*e-mail: zhoujing@tmu.edu.cn; lishaoyong@tmu.edu.cn

1364
Synthesis of N,O-Type Inherently Chiral Calix[4]arenes Substituted on the Lower Rim
J. Braz. Chem. Soc.
column chromatography was performed using silica gel 60.
Optical rotations were measured on a Jasco P-2000 digital
polarimeter. High-resolution mass spectra (HRMS) were
recorded on a 7.0-T (Ionspec, Irvine, CA, USA) Fourier
transform ion cyclotron resonance mass spectrometer.
(m, 14H,Ar-CH2-Ar, O-CH2-CH2-CH3, O-CH2-CH2-O-CH3),
2.92 (s, 3H, O-CH3), 2.46 (s, 3H, Ar-CH3), 1.92-1.78 (m,
2H, O-CH2-CH2-CH3), 1.54 (d, 3H, J 7.2 Hz, CH-CH3), 1.39
(s, 9H, t-Bu), 1.35 (s, 9H, t-Bu), 1.05 (d, 18H, 2t-Bu), 0.97
(t, 3H, J 14.8 Hz, O-CH2-CH2-CH3); 13C NMR (101 MHz,
CDCl3) d 168.6, 153.5, 153.0, 152.5, 147.4, 145.6, 145.5,
145.3, 145.2, 144.5, 144.4, 135.8, 135.4, 134.9, 134.1, 134.0,
131.6, 131.4, 130.2, 129.8, 129.7, 129.5, 128.9, 128.7, 128.4,
128.0, 127.4, 127.0, 126.8, 126.4, 126.2, 125.8, 125.6, 70.0,
69.5, 69.1, 67.7, 67.4, 57.6, 36.9, 36.5, 34.3, 34.2, 33.8,
31.7, 31.6, 31.4, 31.3, 23.8, 21.8, 21.0, 10.7. HRMS (ESI)
m/z, calcd. for C67H87NO8SNa+ 1088.6152 [M + Na]+, found
1088.5779 [M + Na]+.
Synthesis
To a stirred solution of 1a (or 1b)17 (2.00 g, 1.98 mmol) in
tetrahydrofuran (30 mL) was added sodium hydride (0.38 g,
7.9 mmol) at room temperature. The reaction mixture was
heated at reflux for 4 h. Then the 2-methoxyethyl tosylate
was added, and the stir was continued for 2 h and quenched
with hydrocholoric acid (2.00 mol L-1). The aqueous layer
was extracted with dichloromethane, and the combined
organic layers were washed with saturated brine, dried with
anhydrous sodium sulfate. The solvent was removed under
reduced pressure to yield product which was further purified
by silica gel column chromatography (eluent = petroleum
ether:ethyl acetate, 2:1, v/v). Compound 2a (or 2b) was
obtained as white power.
To a stirred solution of 2a (or 2b) (1.50 g, 1.42 mmol)
in butyl alcohol (10 mL) was added potassium tert-butylate
(2 g, 17.8 mmol) at room temperature. When the solid
dissolved, dimethyl sulfoxide (1.50 mL) was added and
the mixture was heated and stirred at 100 °C for 1 h. Then
water (0.05 g, 2 equiv.) was added and heated at reflux for
24 h. The reaction mixture was evaporated to yield black
oily liquid and redissolved in hydrochloric acid (30 mL)
and dichloromethane (30 mL). The aqueous layer was
extracted with dichloromethane (2 × 30 mL), and the
combined organic layers were washed with brine, dried with
anhydrous sodium sulfate, and evaporated to yield brown
oily liquid. The product 3a (or 3b) was further purified
by silica gel column chromatography (eluent = petroleum
ether:ethyl acetate, 3:1, v/v).
2a
Yield: 1.6 g (80%); m.p. 108-111 °C; [a]D25 = +0.1
(c = 1.8 g/100 mL, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.63 (d, 1H, J 8.4 Hz, NH), 7.28 (m, 9H, Ar-H), 7.13 (dd,
2H, J 2.4, 2.4 Hz, Ar-H), 7.09 (dd, 2H, J 2.4, 2.4 Hz, Ar-H),
6.09 (dd, 2H, J 2.4, 2.4 Hz,Ar-H), 6.50 (dd, 2H, J 2.4, 2.4 Hz,
Ar-H), 5.23-5.20 (m, 1H, Ph-CH), 4.55 (d, 1H, J 15.2 Hz,
O-CH2-CO), 4.11 (d, 1H, J 15.2 Hz, O-CH2-CO), 4.00-3.07
(m, 14H,Ar-CH2-Ar, O-CH2-CH2-CH3, O-CH2-CH2-O-CH3),
3.04 (s, 3H, O-CH3), 2.46 (s, 3H, Ar-CH3), 1.84 (m, 2H,
O-CH2-CH2-CH3), 1.53 (d, 3H, J 6.8 Hz, CH-CH3), 1.36
(s, 9H, t-Bu), 1.32 (s, 9H, t-Bu), 1.07 (s, 9H, t-Bu), 1.04
(s, 9H, t-Bu), 0.98 (t, 3H, J 14.8 Hz, O-CH2-CH2-CH3);
13C NMR (101 MHz, CDCl3) d 153.8, 153.6, 147.2, 145.5,
145.2, 145.0, 144.6, 144.2, 140.8, 135.5, 135.4, 134.0, 131.9,
130.5, 129.6, 129.3, 128.7, 128.5, 126.1, 125.7, 125.7, 125.4,
125.1, 125.0, 124.9, 72.8, 71.8, 71.0, 70.4, 58.7, 58.6, 58.3,
37.0, 36.2, 34.4, 34.1, 33.8, 31.7, 31.6, 31.5, 31.4, 31.3, 31.2,
23.8, 21.8, 10.6. HRMS (ESI) m/z, calcd. for C67H87NO8SNa+
1088.6152 [M + Na]+, found 1088.5781 [M + Na]+.
3a
Yield: 0.81 g (54%); m.p. 110-113 °C; [a]D25 = +7.4
1
(c = 6 g/100 mL, CH2Cl2); H NMR (400 MHz, CDCl3)
d 8.15 (s, 1H, COOH), 7.25 (s, 1H, OH), 7.09 (d, 1H, J 2 Hz,
Ar-H), 6.99 (s, 2H,Ar-H), 6.97-6.90 (m, 3H,Ar-H), 6.86 (dd,
2H, J 2.4, 2.4 Hz,Ar-H), 4.85 (d, 1H, O-CH2-CO, J 16.0 Hz),
4.50-3.60 (m, 11H,Ar-CH2-Ar, O-CH2-CH2-O, O-CH2-CO),
3.46 (s, 3H, O-CH3), 3.38-3.21 (m, 4H, O-CH2-CH2-CH3,
O-CH2-CH2-O), 2.10 (m, 2H, O-CH2-CH2-CH3), 1.18 (d,
18H, 2t-Bu), 1.14 (s, 9H, t-Bu), 1.08 (t, 3H, J 14.8 Hz,
O-CH2-CH2-CH3), 1.04 (s, 9H, t-Bu); 13C NMR (101 MHz,
CDCl3) d 171.1, 151.3, 149.2, 147.1, 146.8, 146.0, 142.5,
134.0, 132.8, 129.2, 126.4, 125.9, 125.8, 125.7, 125.6, 125.5,
125.0, 78.9, 74.3, 71.6, 71.5, 58.8, 34.1, 32.3, 31.5, 31.4,
31.3, 31.2, 30.5, 22.8, 10.3. HRMS (ESI) m/z, calcd. for
C52H70O7Na+ 806.5122 [M + Na]+, found 829.5014 [M + Na]+.
2b
Yield: 1.51 g (76%); m.p. 96-98 °C; [a]D25 = −2.4
(c = 2.0 g/100 mL, CH2Cl2); 1H NMR (400 MHz, CDCl3) d
7.67 (d, 1H, J 8 Hz, NH), 7.28 (m, 9H, Ar-H), 7.18 (dd, 2H,
J 2.4, 2.4 Hz,Ar-H), 7.08 (dd, 2H, J 2.4, 2.4 Hz,Ar-H), 6.89
(dd, 2H, J 2.4, 2.4 Hz, Ar-H), 6.48 (dd, 2H, J 2.4, 2.4 Hz,
Ar-H), 5.35-5.25 (m, 1H, Ph-CH), 4.46 (d, 1H, J 14.8 Hz,
O-CH2-CO), 4.11 (d, 1H, J 14.8 Hz, O-CH2-CO), 3.00-4.05
3b
Yield: 0.90 g (60%); m.p. 110-113 °C; [a]D25 = −7.5
(c = 4.5 g/100 mL, CH2Cl2). The relative spectroscopic
data were identical to those of 3a.

Vol. 28, No. 8, 2017
Chang et al.
1365
To a stirring solution of 3a (or 3b) (0.50 g, 0.63 mmol)
in dichloromethane was added O-benzotriazole-
N,N,N’,N’-tetramethyl-uronium-hexafluorophosphate
(0.36 g, 0.95 mmol) followed by the addition of 4-dimethyl
aminopyridine (0.05 g, 0.41 mmol). The reaction
mixture was stirred at room temperature for half an hour.
N,N-Diethylamine was added and stirring was continued
for 6 h at room temperature. The reaction mixture was
quenched with dilute hydrochloric acid and the aqueous
layer was extracted with dichloromethane (2 × 30 mL), and
the combined organic layers were washed with brine, dried
with anhydrous sodium sulfate, and evaporated to dryness.
The product 4a (or 4b) was further purified by silica gel
column chromatography (eluent = petroleum ether:ethyl
acetate, 3:1, v/v).
combined organic layers were washed with brine, dried
with anhydrous sodium sulfate, and evaporated to yield
white liquid. The product 5a (or 5b) was further purified
by silica gel column chromatography (eluent = petroleum
ether:ethyl acetate, 2:1, v/v).
5a
Yield: 0.07 g (33%); m.p. 78-81 °C; [a]D25 = +2.8
(c = 7.5 g/100 mL, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.13 (s, 2H, Ar-H), 7.05 (dd, 2H, J 2.4, 2.4 Hz, Ar-H),
6.52-6.50 (m, 4H, Ar-H), 5.75 (s, 1H, OH), 4.40-4.24 (m,
4H, Ar-CH2-Ar), 4.22-4.05 (m, 4H, Ar-CH2-Ar), 3.92 (m,
2H, O-CH2-CH2-O), 3.87-3.78 (m, 1H, O-CH2-CH2-N),
3.77-3.67 (m, 1H, O-CH2-CH2-N), 3.48 (s, 1H, O-CH3), 3.29-
3.13 (m, 4H, O-CH2-CH2-O, O-CH2-CH2-CH3), 3.04 (m,
2H, O-CH2-CH2-N), 2.62 (m, 4H, N-CH2-CH3), 2.08-1.84
(m, 2H, O-CH2-CH2-CH3), 1.33 (s, 9H, t-Bu), 1.32(s, 9H,
t-Bu), 1.11 (t, 3H, J 14.2 Hz, O-CH2-CH2-CH3), 1.06 (t, 6H,
J14.4 Hz, N-CH2-CH3), 0.83 (s, 9H, t-Bu), 0.81 (s, 9H, t-Bu);
13C NMR (101 MHz, CDCl3) d 151.7, 150.7, 145.8, 145.2,
135.9, 135.8, 132.2, 131.9, 131.8, 129.2, 129.0, 125.7, 125.1,
125.0, 124.9, 124.8, 124.7, 78.1, 74.1, 71.4, 71.1, 58.9, 52.5,
47.8, 34.2, 33.8, 33.7, 33.6, 31.8, 31.7, 31.4, 31.3, 31.1, 31.0,
23.4, 11.8, 10.9. HRMS (ESI) m/z, calcd. for C56H81NO5H+
848.6115 [M + H]+, found 848.6186 [M + H]+.
4a
Yield: 0.32 g (65%); m.p. 96-98 °C; [a]D25 = +5.8
(c = 2.2 g/100 mL, CH2Cl2); 1H NMR (400 MHz, DMSO)
d 7.26 (s, 1H, OH), 7.04 (dd, 2H, J 2.4, 2.4 Hz, Ar-H),
6.98 (dd, 2H, J 2.4, 2.4 Hz, Ar-H), 6.66 (dd, 2H, J 2.4,
2.4 Hz, Ar-H), 6.53 (dd, 2H, J 2.4, 2.4 Hz, Ar-H), 4.72 (d,
1H, J 15.6 Hz, O-CH2-CO), 4.52-4.40 (m, 3H, O-CH2-CO,
Ar-CH2-Ar), 4.37 (d, 1H, Ar-CH2-Ar, J 12.0 Hz), 4.29 (d,
1H,Ar-CH2-Ar, J 12.0 Hz), 3.12 (m, 4H,Ar-CH2-Ar), 3.90-
3.70 (m, 2H, O-CH2-CH2-O), 3.50 (m, 4H, O-CH2-CH2-O,
O-CH2-CH2-CH3), 3.45 (s, 3H, O-CH3), 3.25-3.18 (m, 4H,
N-CH2-CH3), 2.05-1.93 (m, 2H, O-CH2-CH2-CH3), 1.32-
1.15 (m, 24H, t-Bu, N-CH2-CH3), 1.07 (t, 3H, J 14.8 Hz,
O-CH2-CH2-CH3), 0.93 (s, 9H, t-Bu), 0.83 (s, 9H, t-Bu);
13C NMR (101 MHz, CDCl3) d 167.5, 152.8, 152.7, 151.9,
145.0, 144.7, 144.6, 144.4, 139.8, 134.2, 134.0, 133.0,
132.6, 132.5, 132.4, 127.7, 127.4, 125.3, 125.2, 125.1,
124.6, 124.5, 77.0, 73.1, 72.1, 70.7, 58.0, 33.6, 33.4, 33.3,
31.4, 31.2, 30.9, 30.8, 22.7, 14.1, 12.8, 10.5. HRMS (ESI)
m/z, calcd. for C56H79NO6Na+ 861.5907 [M + Na]+, found
884.5804 [M + Na]+.
5b
Yield: 0.08 g (38%); m.p. 78-81 °C; [a]D25 = −2.8
(c = 7.5 g/100 mL, CH2Cl2). The relative spectroscopic
data were identical to those of 5a.
General Henry reaction procedure
6 mmol nitromethane and 0.5 mmol% inherently chiral
calix[4]arene catalyst were mixed and stirred in 4 mL
solvent under nitrogen at an experimental temperature.
After 15 minutes, 0.6 mmol aldehyde was added, and the
mixture was continuously stirred. After completion, the
reaction mixture was removed under reduced pressure. The
crude residue was loaded directly onto a silica gel column
and purified by flash chromatography as described below.
4b
Yield: 0.35 g (71%); m.p. 96-98 °C; [a]D25 = −5.8
(c = 7.5 g/100 mL, CH2Cl2). The relative spectroscopic
data were identical to those of 4a.
2-Nitro-1-(4-nitrophenyl)ethanol
To a solution of 4a (or 4b) (0.20 g, 0.24 mmol)
in tetrahydrofuran (10 mL) was slowly added lithium
aluminum hydride (0.18 g, 4.72 mmol) at 0 °C. After the
mixture was stirred for 5 h at room temperature, the resulting
mixture was filtered and the filtrate was concentrated. The
reaction mixture was redissolved in hydrochloric acid
(10 mL) and dichloromethane (10 mL). The aqueous layer
was extracted with dichloromethane (2 × 10 mL), and the
The title compound was prepared according to the
General experimental procedures section and purified by
column chromatographic purification (CH2Cl2), giving a
1
white solid. H NMR (400 MHz, CDCl3) d 3.20 (s, 1H,
-OH), 4.53-4.69 (m, 2H, -CH2NO2), 5.62 (ddd, J 4.0, 4.1,
8.1 Hz, 1H, -CHOH), 7.65 (d, J 8.7 Hz, 2H, ArH), 8.27 (d,
J 8.7 Hz, 2H, ArH); 13C NMR (101 MHz, CDCl3) d 69.9,
80.6, 124.2, 126.9, 144.9, 148.2.

1366
Synthesis of N,O-Type Inherently Chiral Calix[4]arenes Substituted on the Lower Rim
J. Braz. Chem. Soc.
2-Nitro-1-(4-cyanophenyl)ethanol
7.24-7.29 (m, 2H, ArH), 7.31-7.36 (m, 1H, ArH), 7.42 (s,
1H,ArH); 13C NMR (101 MHz, CDCl3) d 71.8, 84.2, 128.3,
129.3, 130.5, 131.2, 134.2, 146.3.
The title compound was prepared according to the
General experimental procedures section and purified by
column chromatographic purification (CH2Cl2), giving a
white powder. 1H NMR (400 MHz, CDCl3) d 3.31 (s, 1H,
-OH), 4.52-4.62 (m, 2H, -CH2NO2), 5.55 (ddd, J 4.1, 4.2,
8.5 Hz, 1H, -CHOH), 7.57 (d, J 8.3 Hz, 2H, ArH), 7.70 (d,
J 8.3 Hz, 2H, ArH); 13C NMR (101 MHz, CDCl3) d 70.1,
80.6, 112.9, 118.1, 126.7, 132.8, 143.0.
2-Nitro-1-(4-methoxyphenyl)ethanol
The title compound was prepared according to the
General experimental procedures section and purified
by column chromatographic purification (petroleum
1
ether:ethyl acetate, 3:1 v/v) gave a yellow oil. H NMR
(400 MHz, CDCl3) d 2.76 (s, 1H, -OH), 3.81 (s, 3H,
-CH3O), 4.48 (dd, J 2.9, 13.2 Hz, 1H, -CH2NO2), 4.60
(dd, J 9.6, 13.2 Hz, 1H, -CH2NO2), 5.40 (ddd, J 2.9, 4.2,
9.6 Hz, 1H, -CHOH), 6.92 (d, J 8.7 Hz, 2H, ArH), 7.32 (d,
J 8.7 Hz, 2H, ArH); 13C NMR (101 MHz, CDCl3) d 69.9,
80.6, 124.2, 126.9, 144.9, 148.2.
2-Nitro-1-(4-fluorophenyl)ethanol
The title compound was prepared according to the
General experimental procedures section and purified by
column chromatographic purification (CH2Cl2), giving a
colorless oil. 1H NMR (400 MHz, CDCl3) d 2.88 (s, 1H,
-OH), 4.50 (dd, J 3.1, 13.4 Hz, 1H, -CH2NO2), 4.59 (dd,
J 9.4, 13.4 Hz, 1H, -CH2NO2), 5.45 (dd, J 3.1, 9.4 Hz,
1H, -CHOH), 7.06-7.12 (m, 2H, ArH), 7.37-7.42 (m, 2H,
2-Nitro-1-(2-methylphenyl)ethanol
The title compound was prepared according to the
General experimental procedures section and purified
by column chromatographic purification (petroleum
ether:ethyl acetate, 10:1 v/v), giving a dark yellow oil.
1H NMR (400 MHz, CDCl3) d 2.38 (s, 3H, -CH3), 2.69
(s, 1H, -OH), 4.41-4.45 (dd, J 2.8, 13.2 Hz, 1H, -CHOH),
4.51-4.57 (dd, J 9.6, 13.2 Hz, 1H, -CHOH), 5.44 (m, 1H,
-CHOH), 7.20-7.29 (m, 3H,ArH), 7.50-7.53 (m, 1H,ArH);
13C NMR (101 MHz, CDCl3) d 10.1, 68.1, 80.4, 125.8,
127.0, 128.9, 131.1, 134.7, 136.5.
13
ArH); C NMR (101 MHz, CDCl3) d 70.3, 81.1, 116.0,
127.8, 133.8, 162.9.
2-Nitro-1-(2-nitrophenyl)ethanol
The title compound was prepared according to the
General experimental procedures section and purified
by column chromatographic purification (petroleum
ether:ethyl acetate, 5:1 v/v), giving a yellow oil. 1H NMR
(400 MHz, CDCl3) d 3.52 (s, 1H, -OH), 4.56 (dd, J 13.9,
8.8 Hz, 1H, -CH2NO2), 4.84 (dd, J 13.9, 2.2 Hz, 1H,
-CH2NO2), 6.01 (ddd, J 2.2, 4.2, 8.8 Hz, 1H, -CHOH), 7.51-
7.59 (m, 1H, ArH), 7.71-7.79 (m, 1H, ArH), 7.90-7.96 (m,
1H, ArH), 8.02-8.07 (m, 1H, ArH); 13C NMR (101 MHz,
CDCl3) d 69.9, 80.6, 124.2, 126.9, 144.9, 148.2.
Results and Discussion
Synthesis
As shown in Scheme 1, starting from a pair of optically
pure inherently chiral calix[4]arene diastereomers 1a and
1b reported by Kalchenko and co-workers,17 the alkylation
of their last hydroxy groups with 2-methoxyethyl tosylate
readily afforded 2a and 2b in high yields, respectively.Acids
3a and 3b were obtained in moderate yields after the removal
of p-toluenesulfonyl and phenylethylamide of 2a and 2b with
t-BuOK in a mixed solvent, respectively. Diethylamine was
coupled with 3a and 3b, respectively, in dicholomethane
using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU) and 4-dimethylaminopyridine
(DMAP) to produce amides 4a and 4b. The reduction
of 4a and 4b with LiAlH4 in THF gave novel N,O-type
compounds 5a and 5b, respectively. The structures of 2a and
2b, 3a and 3b, 4a and 4b, and 5a and 5b were confirmed
by their 1H NMR, 13C NMR and MS spectra. Their cone or
partial cone conformation is clearly shown in the bridging
2-Nitro-1-(3-nitrophenyl)ethanol
The title compound was prepared according to the
General experimental procedures section and purified by
column chromatographic purification (petroleum ether:ethyl
acetate, 5:1 v/v), giving a brown oil. 1H NMR (400 MHz,
CDCl3) d 3.39 (s, 1H, -OH), 4.58-4.67 (m, 2H, -CH2NO2),
5.60 (dd, J3.3, 9.3 Hz, 1H, -CHOH), 7.56-7.66 (m, 1H,ArH),
7.75-7.79 (m, 1H, ArH), 8.18-8.24 (m, 1H, ArH), 8.28-8.36
(m, 1H, ArH); 13C NMR (101 MHz, CDCl3) d 71.8, 83.2,
123.4, 127.0, 130.3, 137.6, 140.4, 147.6.
2-Nitro-1-(3-chlorophenyl)ethanol
The title compound was prepared according to the
General experimental procedures section and purified
by column chromatographic purification (petroleum
ether:ethyl acetate, 5:1 v/v), giving a dark yellow oil.
1H NMR (400 MHz, CDCl3) d 3.01 (s, 1H, -OH), 4.48-4.60
(m, 2H, -CH2NO2), 5.44 (dd, J 3.9, 13.2 Hz, 1H, -CHOH),
13
methylene signals of their C NMR, respectively.18 Since
1a and 1b have been confirmed as a pair of diastereomers

Vol. 28, No. 8, 2017
Chang et al.
1367
by Kalchenko,17 it is undoubtedly deduced that 2a and
2b are a pair of diastereomers, and 3a ([a]D25 = +7.4) and
3b ([a]D25 = −7.5), 4a ([a]D25 = +5.8) and 4b ([a]D25 = −5.8),
and 5a ([a]D25 = +2.8) and 5b ([a]D25 = −2.8) are three pairs
of enantiomers, respectively.
the excellent yields and notable enantioselectivities were
obtained in 6 h when H2O was added into CH3CN and
THF, respectively (Table 1, entries 1-4). The yields were
not remarkably improved but the enantioselectivities were
slightly enhanced in 6 h when H2O was added into EtOH
(Table 1, entries 7 and 8 versus entries 9 and 10). The
highest enantioselectivity with 7.5% ee was achieved in
a mixed protic solvent (EtOH/H2O, 3:1, v/v) although the
yield was not very high (54%) (Table 1, entry 7). These
catalytic results showed that protic solvents (H2O and
EtOH) are more beneficial to Henry reaction with higher
yield, better enantioselectivity and shorter time than aprotic
solvents (CH3CN and THF). It should be noted that the
absolute configuration of major isomers can be puzzlingly
inverted along solvent change. The absolute configuration
of major isomers using 5a is always S. However, that
of major isomers using 5b is R in THF/H2O, THF and
EtOH (Table 1, entries 4, 6 and 10), and S in CH3CN/
H2O and EtOH/H2O (Table 1, entries 2, 8 and 12). The
absolute configuration inversion of major isomers along
solvent change ever took place in the catalytic asymmetric
addition of diethylzinc to benzaldehyde with inherently
Asymmetric catalysis
The catalytic abilities of 5a and 5b were explored
as chiral organocatalysts for Henry (nitroaldol) reaction
between 4-nitrobenzaldehyde and nitromethane. The
effect of solvent on the reaction was firstly examined at
room temperature. The results from the common different
solvents were summarized in Table 1. It can be seen that
the novel N,O-type organocatalysts 5a and 5b showed
an ability to induce enantioselectivity more or less in
different solvents. We were delighted to find that an
amount of 5 mol% catalysts showed sufficient to achieve
the reaction. The reaction in CH3CN can not afford the
desired product in 48 h (Table 1, entry 5). The yield
(30%) and enantioselectivity (1.6% ee) using 5b were
comparably low in THF in 48 h (Table 1, entry 6). However,
Scheme 1. Synthesis of inherently chiral calix[4]arenes substituted at the lower rim.

1368
Synthesis of N,O-Type Inherently Chiral Calix[4]arenes Substituted on the Lower Rim
J. Braz. Chem. Soc.
Table 1. Optimization of the reaction conditions
entrya
1
Catalyst
5a
Solvent
CH3CN/H2Ob
CH3CN/H2Ob
THF/H2Ob
THF/H2Ob
CH3CNc
Temperature / °C
time / h
Configuration
Yieldd / %
eee / %
7.3
5.4
1.2
4.0
−
rt
rt
6
6
S
S
S
R
−
R
S
R
S
−
S
S
−
−
94
93
99
99
−
2
5b
3
5a
rt
6
4
5b
rt
6
5
5b
rt
48
48
6
6
5b
THF
rt
30
54
63
60
65
84
89
60
61
1.6
7.5
1.1
2.3
0
7
5a
EtOH/H2Ob
EtOH/H2Ob
EtOH
rt
8
5b
rt
6
9
5a
rt
6
10
11
12
13
14
5b
EtOH
rt
6
5a
EtOH/H2Ob
EtOH/H2Ob
EtOH/H2Ob
EtOH/H2Ob
−10
−10
−25
−25
24
24
72
72
0.1
1.2
0
5b
5a
5b
0
aThe reaction was performed with 0.6 mmol 4-nitrobenzaldehyde and 6 mmol nitromethane in 4 mL solvent; bthe volume ratio of the former to the latter
is 3:1; cno desired product; disolated yield; eenantiomeric excess was determined by HPLC using a Chiracel OD-H column. The absolute configurations of
all products were determined by comparing the retention time from HPLC data on the products with those in the literature data.19-21
chiral calix[4]arenes containing quinolin-2-yl-methanol
moiety.2 According to the proposed mechanistic mode
by Deng and co-workers,15 we believe that the aldehyde
is activated by the hydroxyl group through hydrogen
bonding, while the nitromethane is activated by the tertiary
amino group in 5a or 5b catalytic process (Scheme 2). The
more beneficial effect of the protic solvent, especially the
mixed solvent EtOH/H2O, may be plausibly explained
that they can effectively stabilize nitromethide anion and
nitro aldol product through hydrogen bonding interaction.
Lowering reaction temperature has frequently been
reported to enhance the enantioselectivity of Henry
reaction.9-11 With the optimized solvents in hand,
the effect of temperature on enantioselectivity in the
Henry reaction is also studied in a mixed protic solvent
(EtOH/H2O, 3:1, v/v). The results from the different
temperatures (Table 1) showed the enantioselectivity can
not be further improved by lowering the temperature at the
accompanying expense of increasing the reaction time. At
−10 °C, the enantioselectivities became poorer (1.7% ee
using 5a and 1.2% ee using 5b) and the reaction times
were increased to 24 h although the yields were remarkably
improved (Table 1, entries 7 and 8 versus entries 11 and 12).
At −25 °C, the enantioselectivities can not be observed and
the reaction times were further increased to 72 h although
the yield changes were not obvious (Table 1, entries 7 and
8 versus entries 13 and 14).
Under the optimal reaction conditions (5 mol% catalyst,
room temperature and a mixed protic solvent EtOH/H2O),
we then explored a variety of aromatic aldehydes using
the catalyst 5a. Compared to 4-nitrobenzaldehyde, the
aromatic aldehydes bearing electron-withdrawing groups
(4-CN, 4-F, 2-NO2, 3-NO2 and 3-Cl) produced comparable
yields and lower enantiomeric excesses (Table 2, entries
1-5). However, the catalytic results from the aromatic
aldehydes bearing electron-donating groups (4-MeO,
Scheme 2. Proposed mode of action of catalyst 5a.

Vol. 28, No. 8, 2017
Chang et al.
1369
Table 2. 5a-promoted Henry reaction of nitromethane with different aromatic aldehydes
entrya
R
4-CN
time / h
36
Configuration
Yieldc / %
eed / %
2.1
0.2
1.3
1.2
2.7
1.0
−
1
2
3
4
5
6
7
8
S
S
S
S
S
S
−
S
98
85
87
83
80
25
−
4-F
36
2-NO2
3-NO2
3-Cl
12
16
24
4-MeO
4-N(CH3)2b
2-CH3
48
48
48
68
0.5
aThe reaction was performed with 0.6 mmol aromatic aldehyde and 6 mmol nitromethane in 4 mL solvent (EtOH:H2O, 3:1, v/v); bno reaction; cisolated
yield; denantiomeric excess was determined by HPLC using a Chiracel OD-H column. The absolute configurations of all products were determined by
comparing the retention time from HPLC data on the products with those in the literature data.19-21
4-N(CH3)2 and 2-CH3) showed comparatively poorer.
4-Methoxybenzaldehyde and 2-methylbenzaldehyde
only afforded 25% yield and 1.2% ee, and 68% yield and
0.5% ee in 48 h (Table 2, entries 6 and 8). Although a large
quantity of the two substrates remained unreacted, their
reactions were clean, and we did not observe dehydration
to the corresponding nitroalkenes. The reaction with
4-dimethylaminobenzaldehyde can not take place in the
tested condition. These catalytic results clearly showed
that catalyst 5a and the optimized reaction conditions can
be applied in a wide scope of aromatic aldehydes, and
electron-withdrawing groups on aromatic ring are more
beneficial to Henry reaction than electron-donating ones.
In 5a and 5b, the ethylene links and methyl groups
of their catalytic amino groups are free to rotate and
the anchoring phenoxyl group can flap into and away
from the calix cavity. Therefore, it can be conceived that
their catalytic amino groups are also free to rotate. The
nonsatisfactory solvent-dependent enantioselectivity
may mainly be attributed to the high flexibility of their
catalytic amino groups. Reducing the multiple factors of
the high flexibility of the catalytic amino groups will be a
huge challenge in the structural modification of inherently
chiral calix[4]arenes substituted at the lower rim. So many
heavy efforts have been made to structurally modify
inherently chiral calix[4]arenes substituted at the meta
position and the upper rim in Chen and Huang group1,2 and
Shimizu group.3-7 However, the enantioselectivities in their
asymmetric catalysis processes are always poor. Therefore,
the asymmetric catalysis prospects of inherently chiral
calix[4]arenes seem somewhat gloomy.
Conclusions
In conclusion, starting from a pair of reported
inherently chiral calix[4]arene diastereomers, a pair of
N,O-type enantiomers based on inherently chiral calix[4]
arenes substituted at the lower rim were synthesized.
Their organocatalytical behaviors on Henry reaction
between aromatic aldehydes and nitromethane were
studied in different solvent under different temperature.
The aromatic aldehydes bearing electron-withdrawing
groups, a mixed protic solvent and room temperature
are beneficial for the organocatalytic reaction. The
high flexibility of their catalytic amino groups may
mainly result in the nonsatisfactory solvent-dependent
enantioselectivity.
Supplementary Information
Supplementary information (NMR spectra of new
compounds and HPLC spectra) is available free of charge
at http://jbcs.sbq.org.br as PDF file.
Acknowledgments
We thank the National Natural Science Foundation of
China (No. 21272173) for financial support.
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Submitted: September 30, 2016
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