Design, synthesis and application of chiral tetraoxacalix[2]arene[2]triazine-based organocatalysts in asymmetric Michael addition reactions

Article abstract of DOI:10.1002/chir.23055

A novel type of oxacalix[2]arene[2]triazine-based organocatalysts for asymmetric Michael reactions are reported for the first time. Chiral subunits were attached to the heteroatom-bridged calixaromatic platform by a reaction of (R)- and (S)-1-aminotetrali

Full text of DOI:10.1002/chir.23055

Received: 15 November 2018
DOI: 10.1002/chir.23055
Revised: 28 December 2018
Accepted: 2 January 2019
R E G U L A R A R T I C L E
Design, synthesis and application of chiral tetraoxacalix[2]
arene[2]triazine‐based organocatalysts in asymmetric
Michael addition reactions
Hayriye Nevin Genc1
| Ummu Ozgun2 | Abdulkadir Sirit2
1 Department of Science Education,
Ahmet Kelesoglu Education Faculty,
Necmettin Erbakan University, Konya,
Turkey
Abstract
A novel type of oxacalix[2]arene[2]triazine‐based organocatalysts for asymmet-
ric Michael reactions are reported for the first time. Chiral subunits were
attached to the heteroatom‐bridged calixaromatic platform by a reaction of
2 Department of Chemistry, Ahmet
Kelesoglu Education Faculty, Necmettin
Erbakan University, Konya, Turkey
(R)‐ and (S)‐1‐aminotetraline with tetraoxacalix[2]arene[2]triazine in both enan-
tiomeric forms. To evaluate the catalytic efficiency of the novel organocatalysts,
isobutyraldehyde reacted with various substituted and unsubstituted aromatic
trans‐β‐nitrostyrenes in tetrahydrofuran (THF), leading to Michael adducts in
excellent yields and enantioselectivites (up to 97% yield and 99% ee).
Correspondence
Hayriye Nevin Genc, Department of
Science Education, Ahmet Kelesoglu
Education Faculty, Necmettin Erbakan
University, Konya 42090, Turkey.
Email: hngenc@konya.edu.tr
KEYWORDS
asymmetric synthesis, Michael addition, organocatalysis, stereoselectivity, tetraoxacalix[2]arene[2]
triazine
Funding information
Research Foundation of Necmettin
Erbakan University, Grant/Award Num-
ber: BAP–181210007
1 | INTRODUCTION
including oximes, amines, hydroxylamines, nitrile oxides,
aldehydes, ketones, and carboxylic acids.16-18
The Michael reaction, one of the most diverse classes of
reactions that involves a conjugate addition of appropriate
carbanion or nucleophilic reagent to α,β‐unsaturated car-
bonyl compounds, is a useful tool for carbon―nitrogen,
carbon―oxygen, and carbon―carbon bond formations.1-5
The asymmetric version of this reaction using a chiral cat-
alyst is an effective way for the stereoselective construction
of various building blocks6-9 and widely used for the asym-
metric synthesis of pharmaceutical products, chiral drugs,
and biologically active molecules.10-13
The asymmetric Michael addition of ketones, involv-
ing α‐enolizable ketones to electron deficient nitroolefins
has received much attention. Since, these reactions led to
the formation of optically active γ‐nitro carbonyl com-
pounds,14,15 which are found to be important building
blocks in organic/medicinal chemistry. These adducts
play an important role as chiral building blocks and can
be easily transformed to several functional groups
Because of the increasing interest in this area, a wide
range of highly efficient chiral organocatalysts have
appeared in the literature for asymmetric Michael addi-
tions since Barbas and List independently reported the first
organocatalytic studies using L‐proline.19,20 The common
examples include chiral pyrrolidine‐type diamines,21,22
chiral guanidines,23,24 L‐proline derivatives,25,26 chiral
diamines,27,28 Cinchona‐based catalysts,29,30 urea and
thiourea‐derived bifunctional organocatalysts.31,32
In the last decade, we have made considerable efforts
to the synthesis and application of calixarenes. These
cavity‐shaped macrocycles consist of para‐substituted
phenolic units connected to each other by methylene
bridges at 2,6‐positions and are excellent platforms for
the preparation of artificial host molecules with various
functionalities. By comparison to the conventional
calixarenes the oxa‐bridged calixarenes33-35 in that the
aromatic groups are linked each other by heteroatoms
Chirality. 2019;1–8.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

2
GENC ET AL.
instead of methylene units can possess different struc-
tural and chemical properties such as host–guest interac-
tion, molecular recognition, cavity size, etc.36-44
2.1.2 | Procedure for the synthesis of
compound 8a/8b
We have previously described the synthesis and appli-
cation of lower rim‐substituted calix[4]arene derivatives
bearing various functionalities as multiple H‐bond donor
chiral catalysts in stereoselective transformations.45-48
Herein, we report an efficient one‐pot procedure to syn-
thesize both enantiomeric forms of optically active
oxacalix[2]arene[2]triazine and their potential applica-
tion as organic catalysts in the Michael addition of
isobutyraldehyde to various substituted and unsub-
stituted aromatic nitroalkenes under mild conditions. To
the best of the authors' knowledge, the catalytic applica-
tion of the chiral oxacalix[2]arene[2]triazine derivatives
is reported for the first time for the stereoselective
Michael reactions.
A mixture of (R)‐1‐amino tetraline and (S)‐1‐amino
tetraline (0.55 mmol) and DIPEA (1.1 mmol) in THF
(10 mL) was added to a solution of 2,4‐dichloro‐1,3,5‐
triazine 6 (0.25 mmol) in THF (10 mL) at room tempera-
ture The mixture was heated at reflux for 18 to 24 hours,
after which time THF was evaporated under vacuum giv-
ing off solid residue. The residue was separated by apply-
ing flash chromatography using EtOAc/hexane (1:20, v/v)
as eluent to afford the pure products.
Compound 8a/8b (8a)
Crystalline Solid; 80% Yield; α2D5 = −6.5 (C 0.1, CHCL3);
MP 83°C to 85°C; (8b) CRYSTALLINE SOLID; 78%
YIELD; α2D5 = +7.2 (C 0.1, CHCL3); MP 80°C to 82 °C;
1
IR (cm−1): 1491, 1575, 2926, 3236; H NMR (400 MHZ,
CDCL3): Δ = 1.09 to 1.55 (M, 8H), 1.66 to 1.80 (M, 4H),
2.58 to 2.95 (M, 4H), 6.90 to 7.57 (M, 8H), 7.83 (1H). 13C
NMR (100 MHZ, CDCL3): Δ = 18.43, 20.12, 23.07, 28.21,
29.07, 40.55, 48.69, 52.58, 127.12, 128.31, 129.57, 133.14,
137.42; Anal. Calcd. for C23H25N5 (371.47): C, 74.36; H,
6.78; N, 18.85%. Found: C, 74.12; H, 6.75; N, 19.03%.
2 | MATERIALS AND METHODS
2.1 | Synthesis of catalysts
2.1.1 | Procedure for the synthesis of 2a to
2b
2.1.3 | Procedure for direct Michael addi-
tion reaction
Tetraoxa‐bridged calix[2]arene[2]triazine was synthesized
following a procedure published by Wang et al.49,50
A
The α,α‐disubstituted aldehyde (0.15 mmol) was added to
a mixture of catalyst 2a/2b (10% mol) and corresponding
nitroalkene (0.05 mmol) in 0.25 mL solvent. The residue
was separated by applying flash chromatography using
EtOAc/hexane (1:4, v/v) as eluent to afford the pure prod-
ucts. Absolute configurations of the products are known,
and the configuration of the Michael adducts were deter-
mined by comparison with reported data: 5a, c, d, e, f, g,
i,51 5b, h, j.52
mixture of (R)‐1‐amino tetraline or (S)‐1‐amino tetraline
(1.1 mmol) and diisopropylethylamine (DIPEA)
(2.2 mmol) in tetrahydrofuran (THF) (20 mL) was added
to a solution of 1 (0.5 mmol) in THF (20 mL). The mix-
ture was heated at reflux for 24 to 36 hours, after which
time THF was evaporated under vacuum giving off a solid
residue. The residue was separated by applying flash
chromatography using EtOAc/hexane (1:8, v/v) as eluent
to afford the pure products.
(S)‐2,2‐dimethyl‐4‐nitro‐3‐phenylbutanal (5a)
IR (cm−1): 531, 721, 840, 902, 1095, 1218, 1365, 1422,
1714, 2918, 2958, 3010, 3413; 1H NMR (400 MHz, CDCl3):
δ = 1.10 (s, 3H), 1.15 (s, 3H), 3.74 (dd, J = 4.4, 11.5 Hz,
1H), 4.71 (dd, J = 4.4, 13.2 Hz, 1H), 4.80 (dd, J = 11.5,
13.2 Hz, 1H), 7.21 to 7.24 (m, 2H), 7.26 to 7.30 (m, 3H),
9.48 (s,1H); 13C NMR (100 MHz, CDCl3): δ = 18.3, 21.1,
48.4, 76.4, 126.8, 127.3, 128.4, 134.9, 203.8. High‐perfor-
mance liquid chromatography (HPLC) (OD‐H column,
hexane–IPA = 80:20, l = 254 nm, 0.8 mL/min flux,
tr = 18.31 minutes (major); 13.90 minutes (minor).
Compound 2a/2b (2a)
Yellow crystalline solid; 75% Yield; α2D5 = +10.20 (C 1,
CHCL3); MP 176°C to 178°C; (2b) yellow crystalline solid;
73% YIELD; α2D5 = −10.80 (C 1, CHCL3); MP 174°C to
176°C; infrared (IR) (cm−1): 1390, 1475, 1585, 3286; H
1
nuclear magnetic resonance (NMR) (400 MHZ, CDCL3):
Δ = 1.15 to 1.76 (M, 8H), 2.30 to 2.51 (M, 4H), 5.55
(DD, J = 10.5, 3.8 HZ, 2H), 6.59 to 6.68 (M, 4H), 6.71 to
6.79 (M, 4H), 6.80 to 6.90 (M, 6H), 7.25 (D, J = 10.3 HZ,
2H), 8.20 (S, 2H); 13C NMR (100 MHZ, CDCL3):
Δ = 22.0, 23.6, 26.8, 30.4, 33.2, 39.1, 49.2, 61.0, 97.5,
102.9, 105.6, 106.9, 125.6, 136.7, 152.4, 168.4; Anal. Calcd.
for C38H32N8O4 (664.71): C, 68.65; H, 4.86; N, 16.85%.
Found: C, 68.51; H, 4.92; N, 16.90%.
(S)‐3‐(4‐fluorophenyl)‐2,2‐dimethyl‐4‐nitrobutanal (5b)
IR (cm−1): 550, 756, 842, 904, 1235, 1363, 1552, 1715,
2852, 2932, 3009, 3422; 1H NMR (400 MHz, CDCl3):

GENC ET AL.
3
δ = 1.08 (s, 3H), 1.17 (s, 3H), 3.79 (dd, J = 4.3, 11.5 Hz,
1H), 4.74 (dd, J = 4.3, 13.5 Hz, 1H), 4.84 to 4.90 (m,
1H), 7.19 to 7.21 (m, 2H), 7.24 to 7.27 (m, 2H), 9.40 (s,
1H); 13C NMR (100 MHz, CDCl3): δ = 19.3, 22.5, 48.0,
49.3, 76.9, 115.9, 116.6, 132.0, 132.4, 162.5, 164.4, 205.3;
HPLC (OD‐H column, hexane–IPA = 80:20, l = 254 nm,
4.92 (m, 1H), 7.11 to 7.12 (m, 2H), 7.45 to 7.47 (m, 2H),
9.49 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 18.8,
21.4, 47.4, 47.9, 76.0, 121.9, 130.2, 132.0, 134.0, 204.0;
HPLC (OD‐H column, hexane–IPA = 80:20, l = 254 nm,
0.8 mL/min flux, tr
=
21.55 minutes (major);
15.53 minutes (minor).
0.7 mL/min flux, tr
=
30.50 minutes (major);
16.10 minutes (minor).
(S)‐3‐(2‐methoxyphenyl)‐2,2‐dimethyl‐4‐nitrobutanal (5f)
IR (cm−1): 535, 756, 789, 903, 1095, 1217, 1365, 1415, 1560,
1
(S)‐3‐(4‐chlorophenyl)‐2,2‐dimethyl‐4‐nitrobutanal (5c)
1638, 1716, 2845, 2965, 3007, 3415; H NMR (400 MHz,
IR (cm−1): 532, 779, 840, 902, 1017, 1223, 1359, 1495,
CDCl3): δ = 1.01 (s, 3H), 1.06 (s, 3H), 3.78 (s, 3H), 4.11 to
4.14 (br, 1H), 4.62 to 4.66 (dd, J = 4.6, 13.0 Hz, 1H), 4.82
to 4.84 (dd, J = 10.8, 13.0 Hz, 1H), 6.82 to 6.90 (m, 2H),
7.03 to 7.06 (dd, J = 1.7, 7.7 Hz, 1H), 7.20 to 7.25 (m, 1H),
9.48 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 20.0, 21.0,
42.9, 48.6, 55.4, 75.9, 111.4, 120.9, 124.0, 128.8, 128.9,
156.9, 203.8; HPLC (OD‐H column, hexane–IPA = 80:20,
l = 254 nm, 0.8 mL/min flux, tr = 15.10 minutes (major);
10.10 minutes (minor).
1
1559, 1718, 2848, 2967, 3008, 3418; H NMR (400 MHz,
CDCl3): δ = 1.04 (s, 3H), 1.09 (s, 3H), 3.80 (dd, J = 4.0,
11.2 Hz, 1H), 4.71 (dd, J = 4.0, 13.2 Hz, 1H), 4.81 to
4.88 (m, 1H), 7.11–7.15 (m, 2H), 7.30 to 7.32 (m, 2H),
9.48 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 18.7,
21.7, 47.1, 47.8, 76.0, 129.1, 129.9, 134.0, 134.3, 204.1;
HPLC (OD‐H column, hexane–IPA = 80:20, l = 254 nm,
0.8 mL/min flux, tr
=
20.21 minutes (major);
13.60 minutes (minor).
(S)‐3‐(4‐methylphenyl)‐2,2‐dimethyl‐4‐nitrobutanal (5g)
IR (CM−1): 692, 719, 879, 1118, 1382, 1436, 1471, 1548,
1719, 2718, 2818, 2927, 2979; 1H NMR (400 MHZ,
CDCL3): Δ = 1.01 (S, 3H), 1.17 (S, 3H), 2.25 (S, 3H),
3.71 (DD, J = 4.4, 11.6 HZ, 1H), 4.70 (DD, J = 4.4,
13.2 HZ, 1H), 4.79 (DD, J = 11.2, 13.2 HZ, 1H), 7.09 to
7.12 (M, 2H), 7.15 to 7.17 (M, 2H), 9.56 (S, 1H); 13C
NMR (100 MHZ, CDCL3): Δ = 19.1, 21.0, 22.6, 48.0,
49.0, 75.8, 128.7, 131.8, 204.0; HPLC (OD‐H column,
hexane–IPA = 80:20, L = 254 nm, 1.0 ml/min flux,
tr = 15.21 minutes (major); 11.50 minutes (minor).
(S)‐3‐(3‐bromophenyl)‐2,2‐dimethyl‐4‐nitrobutanal (5d)
IR (cm−1): 668, 769, 808, 994, 1073, 1258, 1374, 1480, 1552,
1721, 2723, 2821, 2965; 1H NMR (400 MHz, CDCl3):
δ = 0.89 (s, 3H), 1.09 (s, 3H), 3.63 to 3.69 (dd, J = 4.0,
11.4 Hz, 1H), 4.59 to 4.63 (dd, J = 4.0, 13.4 Hz, 1H), 4.69
to 4.76 (dd, J = 11.5, 13.3 Hz, 1H), 7.10 to 7.20 (m, 2H),
7.28 to 7.29 (m, 1H), 7.33 to 7.36 (m, 1H), 9.39 (s, 1H); 13C
NMR (100 MHz, CDCl3): δ = 19.0, 21.5, 47.8, 48.3, 75.8,
123.1, 128.0, 129.9, 131.0, 132.4, 137.8, 203.5; HPLC (OD‐
H column, hexane–IPA = 80:20, l = 254 nm, 0.8 mL/min
flux, tr = 20.52 minutes (major); 13.81 minutes (minor).
(S)‐2,2‐dimethyl‐4‐nitro‐3‐(2‐nitrophenyl)butanal (5h)
(S)‐3‐(4‐bromophenyl)‐2,2‐dimethyl‐4‐nitrobutanal (5e)
IR (cm−1): 669, 789, 854, 880, 1211, 1310, 1359, 1380,
1441, 1520, 1730, 2721, 2817, 2969; H NMR (400 MHz,
CDCl3): δ = 1.17 (s, 3H), 1.23 (s, 3H), 4.71 (dd, J = 3.6,
11.8 Hz, 1H), 4.81 (dd, J = 3.6, 13.6 Hz, 1H), 4.94 to
5.01 (m, 1H), 7.47 to 7.54 (m, 2H), 7.62 to 7.66 (m, 1H),
1
IR (cm−1): 642, 763, 782, 832, 892, 1074, 1219, 1358, 1485,
1
1563, 1640, 2848, 2932, 3000, 3415; H NMR (400 MHz,
CDCl3): δ = 1.14 (s, 3H), 1.51 (s, 3H), 3.79 (dd, J = 4.3,
11.6 Hz, 1H), 4.71 (dd, J = 4.3, 13.4 Hz, 1H), 4.87 to
SCHEME 1 One‐step procedure for the synthesis of heteroatom‐bridged calixaromatic‐based chiral catalysts 2a and 2b

4
GENC ET AL.
7.86 to 7.88 (m, 1H), 9.54 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 18.9, 20.9, 40.5, 49.2, 75.9, 124.9, 129.0,
131.0, 133.0, 151.4, 203.5. HPLC (AD‐H column,
hexane–IPA = 80:20, l = 254 nm, 0.7 mL/min flux,
tr = 55.20 minutes (major); 33.20 minutes (minor).
TABLE 1 Michael addition between 3 and 4a catalyzed by 2a to
2b in various solvents
(S)‐2,2‐dimethyl‐4‐nitro‐3‐(2‐bromophenyl)butanal (5i)
Entrya Catalyst Solvent
Time (d) Yield (%)b ee (%)c, d
IR (cm−1): 663, 754, 881, 1023, 1377, 1435, 1471, 1553, 1723,
1
2720, 2818, 2973; H NMR (400 MHz, CDCl3): δ = 1.14 (s,
1
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
THF
2
2
4
4
4
4
2
2
3
3
4
4
4
97
96
91
90
89
84
96
94
94
93
89
83
88
98 (S)
97 (R)
89 (S)
88 (R)
85 (S)
83 (R)
98 (S)
95 (R)
95 (S)
92 (R)
84 (S)
82 (R)
87 (S)
3H) 1.19 (s, 3H), 4.65 (dd, J = 4.2, 11.2 Hz, 1H), 4.75 (dd,
J = 4.2, 13.6 Hz, 1H), 4.88 (dd, J = 11.4, 13.2 Hz, 1H), 7.15
to 7.19 (m, 1H), 7.30 to 7.37 (m, 2H), 7.58 (d, J = 8.0 Hz,
1H), 9.56 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 18.8,
20.3, 45.1, 49.2, 75.9, 127.0, 127.9, 128.5, 129.6, 134.0, 135.7,
2
THF
3
CCl4
4
CCl4
5
CH3CN
CH3CN
Et2O
204.1; HPLC (OD‐H column, hexane–IPA
= 80:20,
6
l = 254 nm, 0.8 mL/min flux, tr = 36.30 minutes (major);
14.15 minutes (minor).
7
8
Et2O
9
Toluene
Toluene
DMF
(S)‐3‐(Furan‐2‐yl)‐2,2‐dimethyl‐4‐nitrobutanal (5j)
IR (cm−1): 528, 668, 718, 782, 842, 880, 898, 1010, 1089, 1219,
10
11
12
13
1
1359, 1417; H NMR (400 MHz, CDCl3): δ = 1.13 (s, 3H),
1.19 (s, 3H), 3.89 (dd, J = 4.0, 10.8 Hz, 1H), 4.62 (dd,
J = 4.0, 13.2 Hz, 1H), 4.79 (dd, J = 10.8, 13.0 Hz, 1H), 6.20
to 6.21 (m, 1H), 6.33 to 6.35 (m, 1H), 7.40 (d, J = 1.2 Hz,
1H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 19.0,
21.2, 41.7, 47.7, 75.0, 109.0, 109.9, 142.4, 150.0, 202.9; HPLC
(OD‐H column, hexane–IPA = 80:20, l = 254 nm, 0.7 mL/
min flux, tr = 22.20 minutes (major); 13.20 minutes (minor).
DMF
1,4‐
dioxane
14
2b
1,4‐
dioxane
4
85
85 (R)
15
16
17
18
19
20
21
22
2a
2b
2a
2b
2a
2b
2a
2b
Acetone
Acetone
CHCl3
4
4
4
4
3
3
2
2
90
90
90
89
93
91
95
93
88 (S)
86 (R)
89 (S)
87 (R)
94 (S)
93 (R)
97 (S)
96 (R)
3 | RESULTS AND DISCUSSION
CHCl3
CH2Cl2
CH2Cl2
i‐PrOH
i‐PrOH
To achieve the desired target, we first prepared calix[2]
arene[2]triazine 1 as a starting material by applying a step-
wise strategy according to the literature procedure.48,50 To
synthesize the desired macrocyclic molecules, the reaction
between tetraoxacalix[2]arene[2]triazine 1 and 2.2 equiv of
(R)‐ and (S)‐1‐amino tetraline proceeded efficiently in
diisopropylethylamine DIPEA at room temperature, giv-
ing optically active 2a and 2b as illustrated in Scheme 1.
Based on their spectral data (IR, H NMR, and C NMR),
these compounds were characterized.
Abbreviations: DMF, dimethylformamide; THF, tetrahydrofuran.
aConditions: trans‐β‐nitrostyrene (0.05 mmol), isobutyraldehyde (0.15 mmol),
and 2a/2b (10 mol%) in solvents (0.25 mL).
bIsolated yield after flash chromatography.
cDetermined by HPLC.
dDetermined by comparing reported data.
After having synthesized the tetraoxacalix[2]arene[2]
triazine‐based chiral catalysts, isobutyraldehyde (3) was
initially reacted with trans‐β‐nitrostyrene (4) using 2a
and 2b to further explore the catalytic properties of the
synthesized products.
The reaction was carried out with various solvents to
determine the best solvent under same conditions in the
presence of each chiral catalyst. As summarized in
Table 1, the highest yields and stereoselectivities up to
98% ee were observed when THF was used (Table 1,
entries 1 and 2)
To determine the optimal conditions, Michael reac-
tion was carried out by employing various compounds
as additives or co‐catalysts, but lower yields and ee values
were observed in each case (Table 2).
It is known that reaction temperature is one of the
important factors for better yields and stereoselectivities;
therefore, the addition reaction was repeated using THF
at room temperature, 0°C and −20°C for the enhancement
of catalytic efficiency. The best results were observed at

GENC ET AL.
5
TABLE 2 Additive screening of the 2a and 2b catalyzed Michael
addition of 3 to 4a
TABLE 3 Enantioselective Michael addition catalyzed by 2a, 2b
and 8a, 8b in toluene
Temp.
(°C)
Time
(d)
Yield
(%)b
ee
(%)c, d
Time Yield ee
(d)
Entrya
Catalyst
Entrya Catalyst Additive
(%)b
(%)c, d
1
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
8a
8b
−20
−20
0
6
6
5
5
2
2
3
4
2
2
3
3
4
4
85
82
89
87
97
96
90
88
95
84
93
81
40
35
87 (S)
86 (R)
89 (S)
88 (R)
98 (S)
97 (R)
94 (S)
90 (R)
96 (S)
95 (R)
95 (S)
93 (R)
20 (S)
17 (R)
1
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
None
2
2
5
5
4
4
4
4
4
4
5
5
5
5
97
96
75
70
52
50
65
60
68
65
72
70
69
67
98 (S)
97 (R)
79 (S)
75 (R)
85 (S)
83 (R)
88 (S)
85 (R)
84 (S)
82 (R)
75 (S)
73 (R)
78 (S)
76 (R)
2
2
None
3
3
(S)‐phenyl glycine
(S)‐phenyl glycine
AcOH
4
0
4
5
r.t.
r.t
5
6
6
AcOH
7e
8e
9f
r.t.
r.t
7
p‐TsOH
8
p‐TsOH
r.t.
r.t
9
PhCOOH
PhCOOH
Pyridine
Pyridine
DMAP
10f
11g
12g
13
14
10
11
12
13
14
r.t.
r.t
r.t.
r.t
DMAP
Abbreviation: r.t., room temperature.
Abbreviation: DMAP, dimethylaminopyridine.
aConditions: trans‐β‐nitrostyrene (0.05 mmol), isobutyraldehyde (0.15 mmol),
additive 10 mol%), and 2a/2b or 8a/8b (10 mol%) in tetrahydrofuran
(0.25 mL).
bIsolated yield.
cDetermined by HPLC.
aConditions: trans‐β‐nitrostyrene (0.05 mmol), isobutyraldehyde (0.15 mmol),
additive (10 mol%), and 2a/2b (10 mol%) in tetrahydrofuran (0.25 mL).
bIsolated yield after flash chromatography.
cDetermined by HPLC.
dThe configurations were determined by comparing reported data.
dDetermined by comparing reported data.
eReaction was performed with recycled catalyst.
f15 mol% of catalyst was used.
g5 mol% of catalyst was used.
room temperature compared with at 0°C and −20°C
(Table 3, entries 1‐6).
We also carried out a recycling study of chiral catalyst
2a in the Michael reaction between 3 and 4a (Table 3).
Thus, compound 2a could be easily recycled by flash
chromatography along with Michael adducts after usual
work up. However, by prolonging reaction time, poor
enantioselectivity and yields were observed at room tem-
perature as shown in Table 3 (entries 7 and 8).
The amount of catalyst was increased to a level of
15 mol% and decreased to a level of 5 mol% to evaluate
the influence of catalyst loading on the addition reaction.
In this case, relatively lower stereoselectivities and yields
were observed as depicted in Table 3 (entries 9‐12).
We suppose that the bulky heteroatom‐bridged
calixarene platform attached to the chiral amine plays a
crucial role for steering the process toward the Michael
products in high yields and stereoselectivities. To confirm
this, the monomeric structures 8a and 8b bearing (R)‐
and (S)‐1‐amino tetraline units were prepared by following
the same procedure as illustrated in Scheme 2 and
employed as chiral organocatalysts. In this case, the
Michael reaction resulted with the lower yields and
enantioselectivities (Table 3, entries 13 and 14). The exper-
imental results clearly indicate that the bulky heteroatom‐
bridged calixarene skeleton of the catalysts mainly effects
on the enantioselective addition reaction
According to the results, the optimized conditions were
10 mol% of catalyst loading, room temperature, THF sol-
vent, without additive and 2 days reaction time. These opti-
mized parameters were employed for the reaction of
asymmetric Michael addition of 3 to various substituted
and unsubstituted aromatic nitroalkenes bearing electron‐
donating or electron‐withdrawing groups, affording the
desired Michael adducts 5a to 5j in 80% to 97% yields and

6
GENC ET AL.
4 | CONCLUSION
In conclusion, a novel type of tetraoxa‐bridged calix[2]
arene[2]triazine‐based chiral catalysts 2a and 2b was
developed for the Michael reaction of isobutyraldehyde
to substituted and unsubstituted aromatic nitroalkenes.
The Michael reactions were performed smoothly in THF
at room temperature by employing 10 mol% of 2a, leading
to the Michael adducts in high yields (up to 97%) and ees
(up to 98%).
ACKNOWLEDGMENTS
Financial assistance for this project has been provided by
grants from the Research Foundation of Necmettin
Erbakan University (BAP–181210007).
ORCID
SCHEME 2 Preparation of chiral analogues 8a/8b
Hayriye Nevin Genc
https://orcid.org/0000-0003-3240-
0714
with excellent enantioselectivities (70%‐99%) as demon-
strated in Table 4
Further catalytic studies of the chiral heteroatom‐
bridged calixarene derivatives are now in progress to
explain the mechanism of enantioselective transformation.
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How to cite this article: Genc HN, Ozgun U,
Sirit A. Design, synthesis and application of chiral
tetraoxacalix[2]arene[2]triazine‐based
organocatalysts in asymmetric Michael addition
reactions. Chirality. 2019;1–8. https://doi.org/
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