H. N. Genc, A. Sirit / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
1
O S
4 2
27.2, 127.6, 132.6, 147.3, 149.1, 149.9; Anal. Calcd for C72
(1187.83): C, 72.80; H, 9.33; N, 7.08. Found: C, 71.27; H, 8.56;
N, 8.43.
H
110
N
6
-
4.3. General procedure for direct aldol reaction
To
a stirred mixture of aldehyde (0.07 mmol), catalyst
(
0.007 mmol) and toluene (0.5 mL), acetone (0.7 mmol) was added.
4
.2.2. General procedure for the synthesis of 3a–3b
To a solution of 1a and 1b (0.5 g, 0.46 mmol) in 10 mL dry
CN and K CO (0.29 g, 2.1 mmol) was added benzyl bromide
The reaction was monitored by TLC. Column chromatography of
the crude product on silica gel 60 (230–400 Mesh) using mixture
of ethyl acetate and hexane in varying proportions as eluent, gave
a pure product. The enantiomeric excess of the products was deter-
mined on HPLC using a Chiralpak AS-H and AD-H columns and
mixture of IPA and hexane in different proportions as eluents.
The absolute configuration of the products 12a–j were determined
CH
3
2
3
(
0.31 g, 1.86 mmol) and the resulting mixture was heated at reflux
for 20 h. The reaction mixture was cooled to ambient temperature
and the solvent was removed in vacuo. The residue was dissolved
in dichloromethane (10 mL) and water (10 mL); the organic layer
was separated and the aqueous layer was extracted with dichloro-
methane (3 ꢁ 10 mL). The combined organic layer was dried over
anhydrous MgSO4. After removal of solvent, the crude product
2
2a
22b
22c
by comparison with literature data: 12a,g,j; 12b;
e; 12f, h and 12i.
12c; 12d,
1
3
12
22d
0
was purified by flash chromatography (CHCl
3
–MeOH) to afford
4.3.1. 4-Hydroxy-4-(4 -nitrophenyl)-butan-2-one 12a (entry 1,
Table 4)
3
a–3b.
Compound 12a was prepared according to the general proce-
4
.2.2.1. 25,27-Bis(3-((1R,2R)-2-dibenzylaminocyclohexyl)thio-
dure from 4-NO
2
-benzaldehyde and acetone to provide the title
urea)-26,28-dihydroxy-5,11,17,23-tetra(tert-butyl)-calix[4]arene
and 25,27-bis(3-((1S,2S)-2-dibenzylaminocyclohexyl)thio-
urea)-26,28-dihydroxy-5,11,17,23-tetra(tert-butyl)-calix[4]arene
compound (90% yield) after flash column chromatography on silica
2
0
3
a
D
gel (petroleum ether/ethyl acetate = 5:1). [a] = +60.5 (c 0.02,
ꢀ
1
1
CHCl
(400 MHz, CDCl
COCH CH), 3.56 (s, 1H, CHOH), 5.18–5.21 (m, 1H, CH
(d, J = 8.5 Hz, 2H, CH-Ar), 8.14 (d, J = 8.5 Hz, 2H, CH-Ar); C NMR
(100 MHz, CDCl ): d = 30.7, 38.6, 51.5, 68.8, 123.7, 126.4, 149.9,
3
); IR (cm ): 1363, 1478, 1517, 1718, 2932, 3420; H NMR
): d = 2.15 (s, 3H, COCH ), 2.77–2.81 (m, 2H,
CHC), 7.47
20
3
b.
3a: Crystalline solid; 0.482 g, 73% yield; [
a
]
D
= ꢀ17. 0 (c
3
3
1
, CHCl
3
); mp 196–198 °C; 3b: Crystalline solid; 0.469 g, 71%
2
2
2
0
ꢀ1
13
yield; [
a
]
D
3
= +17.4 (c 1, CHCl ); mp 195–197 °C; IR (cm ): 634,
6
1
61, 698, 871, 943, 981, 1069, 1104, 1123, 1147, 1195, 1235,
3
1
260, 1302, 1361, 1461, 1483, 1585, 1660, 2864, 2950, 3105;
): d = 0.85 (s, 18 H), 0.93–1.12 (m, 8H),
.16 (s, 18 H), 1.38–1.75 (m, 4H), 1.83–2.06 (m, 4H), 2.07–2.29
m, 4H), 2.31–2.62 (m, 8H), 2.72–3.06 (m, 4H), 3.19 (t, 4H,
J = 10.8 Hz), 3.63–4.33 (m, 12 H), 6.67 (s, 4H), 6.92 (s, 8H), 7.14
H
167.7, 208.5; the enantiomeric excess was determined by HPLC
(Chiralcel AS-H), Hexane/i-PrOH 70:30, UV 254 nm, flow rate
1 ml/min, (R)-isomer, t 14.6 min and (S)-isomer, t 16.8 min. 97%
R R
ee.
NMR (400 MHz, CDCl
1
(
3
1
3
0
(
(
6
1
s, 16H), NH- and OH-signals could not be detected; C NMR
100 MHz, CDCl ): d = 23.6, 30.9, 31.4, 33.7, 33.8, 61.4, 62.6,
5.2, 125.0, 125.5, 127.7, 128.0, 128.2, 128.3, 128.7, 132.3,
32.4, 141.8, 147.0, 149.9, 150.0, 160.1, 161.4, 161.6; Anal. Calcd
(1436.11): C, 76.94; H, 8.28; N, 5.85. Found:
C, 75.83; H, 9.32; N, 5.01.
4.3.2. 4-Hydroxy-4-(3 -nitrophenyl)-butan-2-one 12b (entry 2,
Table 4)
3
Compound 12b was prepared according to the general proce-
dure from 3-NO
2
-benzaldehyde and acetone to provide the title
118 6 4 2
for C92H N O S
compound (86% yield) after flash column chromatography on silica
2
0
gel (petroleum ether/ethyl acetate = 7:1). [
a
]
D
= ꢀ56.5 (c 1.2,
); IR (cm ): 1712, 2923, 3087, 3495; H NMR (400 MHz,
): d = 2.15 (s, 3H, COCH ), 2.76–2.88 (m, 2H, COCH CH), 3.59
(s, 1H, CHOH), 5.17 (d, J = 4.4 Hz, 1H, CH CHC), 7.43–8.23 (m, 4H,
): d = 30.7, 51.4, 68.7, 120.7,
ꢀ1
1
CHCl
CDCl
3
4
.2.3. Procedure for the synthesis of chiral p-tert-butylphenol
analogue 8
A solution of 7 (0.04 g, 0.11 mmol) in 10 mL of dry acetonitrile
was stirred for 30 min at room temperature. Acetaldehyde
0.171 g, 3.9 mmol) was then added and the resulting mixture
was stirred for 15 min. NaBH CN (0.049 g, 0.78 mmol) was then
3
3
2
2
1
3
CH-Ar); C NMR (100 MHz, CDCl
3
122.5, 129.5, 131.8, 144.7, 148.3, 208.6; the enantiomeric excess
was determined by HPLC (Chiralcel AS-H), Hexane/i-PrOH 80:20,
UV 254 nm, flow rate 1 ml/min, (R)-isomer, t 11.2 min and (S)-iso-
R
(
3
added, followed 15 min later by AcOH (0.144 mL, 2.52 mmol).
After stirring 4 h at room temperature, the reaction mixture
mer, t
R
13.8 min. 99% ee.
0
3 3
was diluted with 2% CH OH–CH Cl (30 mL), and washed with
4.3.3. 4-Hydroxy-4-(3 -bromophenyl)-butan-2-one 12c (entry 3,
Table 4)
Compound 12c was prepared according to the general proce-
dure from 3-Br-benzaldehyde and acetone to provide the title com-
pound (89% yield) after flash column chromatography on silica gel
1
CHCl
M NaOH (4 ꢁ 25 mL). The aqueous layer was re-extracted with
3
(3 ꢁ 20 mL), and the combined organic layer was dried
. After removal of the solvent, the crude
over anhydrous MgSO
4
3
product was purified by flash chromatography (CHCl –MeOH)
to afford 8.
2
0
(petroleum ether/ethyl acetate = 5:1). [
a
]
D
= ꢀ37.7 (c 1.2, CHCl
IR (cm ): 1712, 2905, 3058, 3426; H NMR (400 MHz, CDCl
d = 2.12 (s, 3H, COCH ), 2.69–2.81 (m, 2H, COCH
1H, CHOH), 5.03 (q, J = 8.2 Hz, 1H, CH CHC), 7.11–7.47 (m, 4H,
): d = 30.7, 51.7, 69.0, 122.6,
3
);
ꢀ1
1
3
):
4
.2.3.1. 1-(3-(4-tert-Butylphenoxy)ethyl)-3-((1S,2S)-2(diethyl-
3
2
CH), 3.37 (br s,
amino)cyclohexyl)thiourea 8.
Yellow oil; 0.037 g, 80% yield;
2
2
0
ꢀ1
13
[
1
a
]
D
= ꢀ5.1 (c 1, CHCl
608, 2870, 2932, 2959, 3303;
d = 1.15–1.40 (m, 12H), 1.70–2.22 (m, 5H), 2.18 (s, 6H), 2.50–2.79
m, 2H), 2.81–3.15 (m, 3H), 3.22–3.67 (m, 3H), 3.65–3.84 (m,
H), 3.90–4.22 (m, 2H), 6.75–6.87 (m, 2H), 7.20–7.44 (m, 2H),
3
); IR (cm ): 735, 1065, 1242, 1362, 1512,
CH-Ar); C NMR (100 MHz, CDCl
3
1
H
NMR (400 MHz, CDCl
3
):
124.2, 128.7, 130.1, 130.6, 145.1, 208.8; the enantiomeric excess
was determined by HPLC (Chiralcel AD-H), Hexane/i-PrOH 95:5,
UV 254 nm, flow rate 1 ml/min, (R)-isomer, t 14.5 min and (S)-iso-
R
(
2
mer, t
R
16.4 min. 86% ee.
13
NH-signals could not be detected; C NMR (100 MHz, CDCl
d = 11.9, 23.5, 23.6, 27.3, 31.5, 31.5, 61.8, 64.7, 113.8, 113.8,
26.1, 126.5, 144.3, 155.6, 159.7; Anal. Calcd for C24 OS
419.67): C, 68.69; H, 9.85; N, 14.01. Found: C, 67.30; H, 10.85;
N, 14.40.
3
):
0
4.3.4. 4-Hydroxy-4-(2 -bromophenyl)-butan-2-one 12d (entry 4,
Table 4)
Compound 12d was prepared according to the general
procedure from 2-Br-benzaldehyde and acetone to provide the title
1
(
41 3
H N