Novel and highly efficient bifunctional calixarene thiourea derivatives as organocatalysts for enantioselective Michael reaction of nitroolefins with diketones

Article abstract of DOI:10.1007/s10847-017-0761-1

New bifunctional calixarene thiourea organocatalysts were synthesized and applied in catalytic asymmetric Michael addition of acetylacetone to various nitroolefins at room temperature. The corresponding adducts were obtained in good to excellent yields wi

Full text of DOI:10.1007/s10847-017-0761-1

J Incl Phenom Macrocycl Chem
DOI 10.1007/s10847-017-0761-1
ORIGINAL ARTICLE
Novel and highly efficient bifunctional calixarene thiourea
derivatives as organocatalysts for enantioselective Michael
reaction of nitroolefins with diketones
Hayriye Nevin Genc · Abdulkadir Sirit1
1
Received: 14 April 2017 / Accepted: 31 October 2017
©
Springer Science+Business Media B.V., part of Springer Nature 2017
Abstract New bifunctional calixarene thiourea organocat-
alysts were synthesized and applied in catalytic asymmetric
Michael addition of acetylacetone to various nitroolefins at
room temperature. The corresponding adducts were obtained
in good to excellent yields with excellent enantioselectivi-
ties (up to 92% ee). The present research demonstrates the
advantages of incorporating two stereocontrolling structures
into a single catalyst. Notably, it offers a simple and conveni-
ent doubly stereocontrolled approach for the catalytic asym-
metric synthesis of a chiral organic molecule.
Michael addition to electron deficient nitroolefins is one
of the important reactions in organic synthesis that access
to synthetically useful functionalized nitroalkanes [9]. Also
the direct asymmetric Michael addition of carbon nucleo-
philes, such as aldehydes, ketones, and methylene-active
substrates, to nitroolefins is one of the most attractive and
atom-economical processes to access functionalized enan-
tiomerically enriched nitroalkanes, and impressive progress
was recently made in this area [10]. In contrast, the use of
chiral bifunctional thioureas as powerful hydrogen-bond-
donating organocatalysts for the synthesis of optically active
compounds has become a new and exciting area of contem-
porary synthetic organic chemistry [11] since Jacobsen suc-
cessfully develop an effective chiral Schiff base–thiourea
catalyzed asymmetric Strecker reaction [12].
Keywords Calixarenes · Asymmetric Michael addition
reactions · Thiourea · Organocatalysis · Enantioselectivity
Introduction
Calixarenes compose an important category of macro-
cyclic compound on account of their potential for forming
host–guest complexes with varied classes of compounds in
supramolecular chemistry [13]. The sites accesible on these
macrocyclic compounds can be simply modified to tailor
them for a great deal applications, such as phase-transfer
catalysts, ionophores in catalysis, carriers in liquid mem-
brane technology, heavy metal adsorption agents, alkali
metal complexation agents, extractants for anions and cati-
ons, and chemical sensors [14]. The most popular chiral
building blocks used, amino acids [15], peptides [16], amino
alcohols [17], sugars [18], tartaric acid esters [19], binaph-
thyl [20], menthone [21], and guanidinium [22] groups offer
a wide range of possibilities for providing calix [4] arenes
with asymmetric features.
Recently, the design and application of organocatalysts have
sustained much attention due to asymmetric organocatalysis
emerging as an effective and environmentally friendly meth-
odology for the catalytic production of the valuable synthetic
building blocks. The chiral information in the catalyst has
been placed at both the nitrogen terminus in the urea or thio-
urea or in the central chiral core [1]. In this respect [2], a few
structures are used in the preparation of the catalysts, namely
chiral diamines [3], both enantiomers of trans cyclohexane-
1
,2-diamine [4], binaphthyl amines [5], diamines derived
from cinchona alkaloids [6], amino alcohols [7] and very
recently, sugars [8].
Thus, chiral calix [4] arene derivatives obtained in this
way not only provide a controlled means for studying the
fundamentals of non-covalent interactions in nature, but also
open up new routes for developing novel enantioselective
sensors, asymmetric catalysts, selectors and other molecular
*
Abdulkadir Sirit
asirit@konya.edu.tr
1
Department of Chemistry, Necmettin Erbakan University,
4
2090 Konya, Turkey
Vol.:(0
1
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3

J Incl Phenom Macrocycl Chem
devices [23]. In the past few years, a series of thiourea-based
catalysts were designed and synthesized because of their
strong hydrogen-bonding activity and effectively catalyzed
various types of asymmetric reactions. Impressive progress
has been made in the development of new, readily avail-
able chiral organocatalysts. We had previously reported the
synthesis of novel chiral calix [4] arenes containing various
functionalities as organocatalysts and their catalytic activi-
ties in asymmetric Michael addition of aldehydes to nitroalk-
enes and maleimides [24–26]. Herein, we report the synthe-
sis of calixarene-based chiral bifunctional organocatalysts
bearing tertiary amine–thiourea moiety in both enantiomeric
forms and their application in the catalytic conjugate addi-
tion of acetylacetone to nitroolefins.
After stirring 1 day at room temperature, the reaction
mixture was diluted with 2% CH OH-CH Cl (150 mL),
3
3
washed with 1N NaOH (4 × 45 mL). The aqueous layer
was re-extracted with CHCl (3 × 30 mL), the combined
3
organic layer was dried over anhydrous MgSO . The crude
4
product was directly loaded onto a silica gel column.
Flash column chromatography using the indicated eluent
(CHCl –MeOH) afforded the 2a–2b.
3
25,27‑Bis(3‑((1R,2R)‑2‑dipropylaminocyclohexyl)
thiourea)‑26,28‑dihydroxy‑5,11,17,23‑tetra(tert‑butyl)
‑calix [4] arene (2a) and 25,27‑Bis(3‑((1S,2S)‑2‑dipro‑
pylaminocyclohexyl)thiourea)‑26,28‑dihydroxy‑5,11,17,
2
3‑tetra(tert‑butyl)‑calix [4] arene (2b)
2
5
Experimental
General
(2a) Crystalline solid; 1.287 g, 75% yield; α + 3.32 (c
D
1
, CHCl ); mp 175–177 °C; (2b) Crystalline solid; 1.236
3
25
g, 72% yield; α − 3.54 (c 1, CHCl ); mp 174-176 °C; IR
D
3
−
1
(
cm ): 595, 664, 752, 818, 870, 944, 1045, 1094, 1123,
1
IR spectra were obtained on a Termo Scientific Nicolet
iS5 FTIR spectrometer equipped with an ATR unit and are
1360, 1539, 1634, 2863, 2929, 2952, 3273; H NMR (400
MHz, CDCl ): δ = 0.78–1.01 (m, 12H), 1.01 (s, 18H),
3
−1
reported in wavenumbers (cm ). Melting points were deter-
mined on an Electrothermal 9100 apparatus in a sealed cap-
illary. Optical rotations were obtained on an Atago AP-100
1.02–1.23 (m, 8H), 1.24 (s, 18H), 1.36–1.84 (m, 8H),
1.87–2.15 (m, 4H), 2.18–2.42 (m, 8H), 2.43–2.64 (m, 8H),
2.65–3.21 (m, 4H), 3.34 (d, 4H, J = 13.0 Hz), 3.74–4.01
(m, 8H), 4.03 (d, 4H, J = 13.2 Hz), 6.67 (s, 4H), 7.03 (s,
4H), 7.99 (bs, 2H), NH-signals could not be detected;
1
13
digital polarimeter. H NMR (400 MHz) and C NMR
(
100 MHz) spectra were obtained at room temperature using
1
3
CDCl as solvent and chemical shifts are reported in sppm.
C NMR (100 MHz, CDCl ): δ = 11.5, 11.6, 16.5, 23.7,
3
3
Data are reported as follows: chemical shift (ppm), mul-
tiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
br=broad), and coupling constants (Hz). Chiral HPLC anal-
ysis was carried out on Agilent 1100 equipment connected
with Chiralpak Daicel AD-H and AS-H columns. Elemental
analyses were performed using a Leco CHNS-932 analyzer.
Crude products were purified by column chromatography on
silica gel of 230–400 mesh. All solvents and reagents were
purified by standard techniques.
24.4, 24.6, 31.0, 31.1, 31.4, 31.6, 33.8, 33.9, 125.1, 125.2,
125.4, 125.6, 132.5, 132.6, 136.1, 141.2, 141.5, 142.04,
146.92, 149.52, 150.4; Anal. Calcd. For C H N O S
4 2
7
6
118
6
(1243.94): C, 73.38; H, 9.56; N, 6.76%. Found: C, 73.54;
H, 9.32; N, 6.51%.
General procedure for the synthesis of 3a–3b
To a solution of 1a and 1b (0.5 g, 0.46 mmol) in 10 mL
Synthesis of catalysts
dry CH CN and K CO (0.29 g, 2.1 mmol) was added
3
2
3
3
-phenylpropanal (0.25 g, 1.86 mmol) and the resulting
Chiral catalysts 1a–1b and chiral p-tert-butylphenol deriva-
tives 8, 9 and 10 were obtained following the literature pro-
cedure [25].
mixture was heated to reflux for 32 h. The reaction mixture
was allowed to warm slowly to room temperature and the
solvent was removed in vacuo. The residue was dissolved
in dichloromethane (10 mL) and water (10 mL); the aque-
ous phase was separated and extracted with dichlorometh-
ane (3 × 10 mL). The combined organic layer was dried
General procedure for the synthesis of 2a–2b and 3a–3b
The solution of 1a or 1b (1.484 g 1.38 mmol) in 20 mL
dry acetonitrile was stirred for 30 min at room tempera-
ture. Propionaldehyde (0.936 g, 16.13 mmol) was then
added and the resulting mixture was stirred for 15 min.
over anhydrous MgSO . The crude product was directly
4
loaded onto a silica gel column. Flash column chromatog-
raphy using the indicated eluent (CHCl –MeOH) afforded
3
the 3a–3b.
NaBH CN (0.596 g, 9.49 mmol) was then added, fol-
3
lowed 15 min later by AcOH (0.025 mL, 0.44 mmol).
1
3

J Incl Phenom Macrocycl Chem
2
5,27‑Bis(3‑((1R,2R)‑2‑(bis(3‑phenylpropyl))
24.2, 24.3, 28.6, 31.5, 32.4, 34.1, 38.5, 113.9, 120.3, 143.7,
156.2; Anal. Calcd. For C H N OS (447.72): C, 69.91;
amino cyclohexyl)thiourea)‑26,28‑dihydroxy‑
2
6
45
3
5
,11,17,23‑tetra(tert‑butyl)‑calix [4] arene(3a)
H, 10.13; N, 9.41%. Found: C, 69.62; H, 10.05; N, 9.62%.
and 25,27‑Bis(3‑((1S,2S)‑2‑(bis(3‑phenylpropyl)amino‑
cyclohexyl)thiourea))‑26,28‑dihydroxy‑5,11,17,23‑tetra(t
ert‑butyl)‑calix [4] arene(3b)
General procedure for direct Aldol reaction
Acetylacetone 5 (0.1 mmol) was added to a mixture of
catalyst (10 mol%) and the corresponding nitroolefin 4
2
5
(
3a) Crystalline solid; 0.541 g, 76% yield; α − 3.94 (c
D
1
, CHCl ); mp 116–118 °C; (3b) Crystalline solid; 0.534
3
(
0.05 mmol) in CH CN (125 µL). The reaction mixture was
3
25
g, 75% yield; α + 4.00 (c 1, CHCl ); mp 119–121 °C;
D
3
stirred at room temperature for the required time. After the
nitroolefin was consumed by TLC analysis, the residue was
separated by flash chromatography over silica gel (petroleum
ether/ethyl acetate) to give Michael adduct. The enantio-
meric excess was determined by chiral HPLC with Daicel
Chiralpak AD-H or AS-H columns. The absolute configu-
ration of the products 6a–j was determined by comparison
with literature data: 6a [1, 9], 6b, c, d, e [1], 6f [27], 6 g
−
1
IR (cm ): 562, 590, 660, 745, 780, 818, 871, 943, 1045,
1
2
1
2
2
8
123, 1195, 1298, 1360, 1452, 1483, 1544, 1601, 1667,
1
860, 2948, 3266; H NMR (400 MHz, CDCl ): δ=1.02 (s,
3
8H), 1.09–1.26 (m, 8H), 1.29 (s, 18H), 1.45–2.01 (m, 12H),
.11–2.38 (m, 8H), 2.40–2.64 (m, 8H), 2.65–2.84 (m, 8H),
.90–3.15 (m, 4H), 3.33 (d, 4H, J=13.2 Hz), 3.66–4.38 (m,
H), 4.41 (d, 4H, J=13.6 Hz), 6.74–7.10 (m, 8H), 7.14–7.40
(
m, 20H), 7.88 (bs, 2H), NH-signals could not be detected;
[
28], 6 h [29], 6i [30], 6j [31].
1
3
C NMR (100 MHz, CDCl ): δ = 24.6, 29.7, 31.0, 31.9,
3
3
1
1
1
2.0, 32.4, 33.5, 33.8, 34.4, 36.5, 50.3, 64.5, 65.6, 125.1,
25.6, 125.7, 128.4, 128.8, 129.0, 132.1, 132.6, 136.8,
39.4, 141.6, 142.1, 142.5, 142.7, 147.1, 147.5, 148.8,
(S)‑3‑(2‑Nitro‑1‑phenylethyl)pentane‑2,4‑dione (6a)
This compound was obtained from β-nitrostyrene and acet-
ylacetone to provide the title compound (97% yield) and
purified by flash chromatography (petroleum ether/ethyl
49.5, 150.4, 159.9, 161.9; Anal. Calcd. for C
H
N O S
1
00 134 6 4 2
(
1548.33): C, 77.57; H, 8.72; N, 5.43%. Found: C, 77.32; H,
.51; N, 5.65%
8
2
5
−1
acetate = 5:1). α : + 196.2 (c = 1.0, CHCl ); IR (cm ):
D
3
1
7
02, 1142, 1269, 1365, 1433, 1496, 1555, 1703, 1732; H
Procedure for the synthesis of chiral p‑tert‑butylphenol
NMR (400 MHz, CDCl ): δ=1.87 (s, 3H, COCH ), 2.23 (s,
3
3
analogue 11
3
H, COCH ), 4.21–4.17 (m, 1H, ArCHCH ), 4.30 (d, 1H,
3
2
J=10.5 Hz, COCHCO), 4.58–4.55 (m, 2H, CHCH NO ),
2
2
The solution of 10 (0.04 g, 0.11 mmol) in 10 mL dry ace-
tonitrile was stirred for 30 min at room temperature. Pro-
pionaldehyde (0.226 g, 3.9 mmol) was then added and
1
3
7
.12–7.10 (m, 2H, ArH), 7.26–7.19 (m, 3H, ArH);
C
NMR (100 MHz, CDCl ): δ=29.6, 30.5, 42.7, 70.7, 78.2,
3
1
27.9, 128.6, 129.3, 135.9, 201.0, 201.8; The enantiomeric
the resulting mixture was stirred for 15 min. NaBH CN
3
excess was determined by HPLC (Chiralcel AS-H), Hexane:
(
0.049 g, 0.78 mmol) was then added, followed 15 min
i-PrOH 85:15, UV 210 nm, flow rate 1 mL/min, R-isomer, t
R
later by AcOH (0.144 mL, 2.52 mmol). After stirring 4 h
at room temperature, the reaction mixture was diluted
with 2% CH OH–CH Cl (30 mL), washed with 1N NaOH
2
2.39 min and S-isomer, t 14.43 min. 81% ee.
R
3
3
(
4×25 mL). The aqueous layer was re-extracted with CHCl
(S)‑3‑[1‑(2‑Bromophenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
3
(
3 × 20 mL), the combined organic layer was dried over
one (6b)
anhydrous MgSO . The crude product was directly loaded
4
onto a silica gel column. Flash column chromatography
This compound was obtained from 2-Br-β-nitrostyrene and
acetylacetone to provide the title compound (65% yield) and
purified by flash chromatography (petroleum ether/ethyl ace-
using the indicated eluent (CHCl –MeOH) afforded the 11.
3
2
5
−1
1
‑(3‑(4‑tert‑butylphenoxy)propyl)‑3‑((1S,2S)‑2(diethyla
tate = 6:1). α : +209.3 (c = 1.0, CHCl ); IR (cm ): 765,
3
D
1
mino)cyclohexyl) thiourea (11)
1152, 1260, 1359, 1433, 1469, 1553, 1705, 1727; H NMR
(
400 MHz, CDCl ): δ=2.04 (s, 3H, COCH ), 2.29 (s, 3H,
3
3
2
5
Yellow oil; 0.037 g, 75% yield; α −7.00 (c 1, CHCl ); IR
COCH ), 4.59 (d, J=9.4 Hz, 1H, COCHCO), 4.68–4.64 (m,
D
3
3
−
1
(
cm ): 731, 1036, 1241, 1383, 1512, 1644, 2865, 2948,
1H, ArCHCH ), 4.85–4.71 (m, 2H, CHCH NO ), 7.19–7.12
2
2
2
1
3
0
1
6
138; H NMR (400 MHz, CDCl ): δ=0.36–0.60 (m, 12H),
(m, 2H, ArH), 7.30–7.26 (m, 1H, ArH), 7.63 (d, J=7.9 Hz,
3
1
3
.74–0.94 (m, 11H), 1.00–1.29 (m, 2H), 1.31–1.53 (m, 3H),
.51–1.75 (m, 3H), 3.10–3.48 (m, 4H), 3.52–3.70 (m, 4H),
.39–6.60 (m, 2H), 6.61–7.05 (m, 2H), NH-signals could not
1H, ArH); C NMR (100 MHz, CDCl ): δ = 28.3, 30.9,
3
41.0, 69.1, 76.2, 128.3, 129.9, 134.0, 135.0, 200.8, 201.9;
The enantiomeric excess was determined by HPLC (Chi-
ralcel AD-H), Hexane: i-PrOH 97:3, UV 210 nm, flow
1
3
be detected; C NMR (100 MHz, CDCl ): δ=10.6, 11.3,
3
1
3

J Incl Phenom Macrocycl Chem
1
3
rate 0.5 mL/min, R-isomer, t 27.30 min and S-isomer, t
1H, ArH), 7.29–7.24 (m, 1H, ArH); C NMR (100 MHz,
R
R
2
2.44 min. 90% ee.
CDCl ): δ=28.7, 29.7, 30.4, 38.9, 55.4, 69.1, 111.2, 121.2,
3
1
23.5, 129.7, 130.2, 201.5, 202.3, The enantiomeric excess
(
S)‑3‑[1‑(3‑Bromophenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
was determined by HPLC (Chiralcel AS-H), Hexane:
i-PrOH 97:3, UV 210 nm, flow rate 0.5 mL/min, R-isomer,
t 42.17 min and S-isomer, t 40.59 min. 92% ee.
one (6c)
R
R
This compound was obtained from 3-Br-β-nitrostyrene
and acetylacetone to provide the title compound (72%
yield) and purified by flash chromatography (petroleum
(S)‑3‑[1‑(4‑Methoxyphenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
one (6f)
2
5
ether/ethyl acetate = 6:1). α : +132.6 (c = 1.0, CHCl );
D
3
−
1
IR (cm ): 699, 790, 1141, 1252, 1367, 1383, 1433, 1477,
This compound was obtained from 4-MeO-β-nitrostyrene
and acetylacetone to provide the title compound (95%
yield) and purified by flash chromatography (petroleum
1
1
550, 1703, 1727; H NMR (400 MHz, CDCl ): δ = 2.00
3
(
s, 3H, COCH ), 2.29 (s, 3H, COCH ), 4.23–4.18 (m, 1H,
3
3
2
5
ArCHCH ), 4.33 (d, J=10.6 Hz, 1H, COCHCO), 4.63–4.61
ether/ethyl acetate=5:1). α : +119.7 (c=2.5, CHCl ); IR
3
2
D
−
1
(
m, 2H, CHCH NO ), 7.26–7.11 (m, 2H, ArH), 7.35 (s, 1H,
(cm ): 812, 1141, 1171, 1261, 1363, 1438, 1515, 1549,
2
2
1
3
1
ArH), 7.43 (d, J=8.9 Hz, 1H, ArH); C NMR (100 MHz,
1614, 1705, 1733; H NMR (400 MHz, CDCl ): δ=1.93 (s,
3
CDCl ): δ = 29.8, 30.5, 42.3, 70.3, 77.7, 123.3, 126.6,
3H, COCH ), 2.28 (s, 3H, COCH ), 3.76 (s, 3H, ArOCH ),
3
3
3
3
1
30.8, 131.0, 131.8, 138.5, 200.4, 201.3; The enantiomeric
4.21–4.15 (m,1H, ArCHCH ), 4.32 (d, J = 10.9 Hz, 1H,
2
excess was determined by HPLC (Chiralcel AD-H), Hexane:
COCHCO), 4.58–4.55 (m, 2H, CHCH NO ), 6.83 (d,
2
2
1
3
i-PrOH 85:15, UV 210 nm, flow rate 1 mL/min, R-isomer, t
J = 8.8 Hz, 2H, ArH), 7.09 (d, J = 8.7 Hz, 2H, ArH);
C
R
3
4.26 min and S-isomer, t 17.67 min. 83% ee.
NMR (100 MHz, CDCl ): δ=29.5, 30.4, 42.1, 55.2, 70.8,
3
R
7
8.4, 114.6, 127.6, 129.0, 159.4, 201.2, 201.9; The enantio-
(
S)‑3‑[1‑(4‑Bromophenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
meric excess was determined by HPLC (Chiralcel AD-H),
Hexane: i-PrOH 90:10, UV 210 nm, flow rate 1 mL/min,
R-isomer, t 23.70 min and S-isomer, t 15.53 min. 82% ee.
one (6d)
R
R
This compound was obtained from 4-Br-β-nitrostyrene
and acetylacetone to provide the title compound (81%
yield) and purified by flash chromatography (petroleum
(R)‑3‑[1‑(4‑Fluorophenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
one (6g)
2
5
ether/ethyl acetate = 5:1). α : +137.1 (c = 1.0, CHCl );
D
3
−
1
IR (cm ): 818, 1140, 1264, 1362, 1431, 1490, 1547,
This compound was obtained from 4-F-β-nitrostyrene and
acetylacetone to provide the title compound (85% yield)
and purified by flash chromatography (petroleum ether/
1
1
3
699, 1729; H NMR (400 MHz, CDCl ): δ = 1.98 (s,
3
H, COCH ), 2.30 (s, 3H, COCH ), 4.24–4.18 (m, 1H,
3
3
2
5
−1
ArCHCH ), 4.33 (d, J=10.8 Hz, 1H, COCHCO), 4.61–4.59
ethyl acetate = 5:1). α : +12.9 (c = 1, CHCl ); IR (cm ):
3
2
D
(
(
m, 2H, CHCH NO ), 7.07 (d, J=8.4 Hz, 2H, ArH), 7.46
827, 1141, 1267, 1363, 1437, 1513, 1550, 1704, 1733;
2
2
1
3
1
d, J = 8.5 Hz, 2H, ArH); C NMR (100 MHz, CDCl ):
H NMR (400 MHz, CDCl ): δ = 1.96 (s, 3H, COCH ),
3
3
3
δ=29.7, 30.5, 42.2, 70.4, 77.8, 122.7, 129.6, 132.5, 135.0,
2.29 (s, 3H, COCH ), 4.26–4.21 (m, 1H, ArCHCH ),
2
3
2
00.6, 201.4; The enantiomeric excess was determined
by HPLC (Chiralcel AS-H), Hexane: i-PrOH 85:15, UV
10 nm, flow rate 1 mL/min, R-isomer, t 30.29 min and
4.33 (d, J = 10.8 Hz, 1H, COCHCO), 4.61–4.59 (m, 2H,
CHCH NO ), 7.04–6.99 (m, 2H, ArH), 7.19–7.15 (m, 2H,
2
2
1
3
2
ArH); C NMR (100 MHz, CDCl ): δ = 29.6, 30.5, 42.0,
R
3
S-isomer, t 16.79 min. 83% ee.
70.6, 78.1, 116.3, 116.5, 129.6, 129.7, 131.7, 161.2, 163.7,
R
2
00.8, 201.5; The enantiomeric excess was determined
(
R)‑3‑[1‑(2‑Methoxyphenyl)‑2‑nitroethyl]pen‑
by HPLC (Chiralcel AD-H), Hexane: i-PrOH 90:10, UV
tane‑2,4‑dione (6e)
210 nm, flow rate 1 mL/min, R-isomer, t 26.08 min and
R
S-isomer, t 13.28 min. 79% ee.
R
This compound was obtained from 2-MeO-β-nitrostyrene
and acetylacetone to provide the title compound (93% yield)
and purified by flash chromatography (petroleum ether/ethyl
(R)‑3‑[1‑(4‑Methylphenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
one (6h)
2
5
−1
acetate=4:1). α : −186.1 (c=1.0, CHCl ); IR (cm ): 758,
D
3
1
1
024, 1159, 1247, 1359, 1494, 1552, 1596, 1702, 1727; H
This compound was obtained from 4-Me-β-nitrostyrene
and acetylacetone to provide the title compound (89%
yield) and purified by flash chromatography (petroleum
NMR (400 MHz, CDCl ): δ = 1.93 (s, 3H, COCH ), 2.28
3
3
(
s, 3H, COCH ), 3.88 (s, 3H, ArOCH ), 4.51–4.45 (m, 1H,
3
3
2
5
COCHCO), 4.61–4.56 (m, 2H, CHCH NO ), 4.86–4.75 (m,
ether/ethyl acetate = 6:1). α : − 78.2 (c = 2.8, CHCl ); IR
3
2
2
D
−
1
1
1
H, ArCHCH ), 6.91–6.87 (m, 2H, ArH), 7.09–7.07 (m,
(cm ): 813, 1140, 1267, 1362, 1430, 1548, 1702, 1731; H
2
1
3

J Incl Phenom Macrocycl Chem
NMR (400 MHz, CDCl ): δ = 1.94 (s, 3H, COCH ), 2.29
1b with propionaldehyde and 3-phenyl propanal according
to the method reported by us [25] in 72–76% yields as
shown in Scheme 1.
3
3
(
s, 6H, COCH + ArCH ), 4.23–4.17 (m, 1H, ArCHCH ),
3
3
2
4
.33 (d, J = 10.8 Hz, 1H, COCHCO), 4.61–4.58 (m, 2H,
13
1
CHCH NO ), 7.13–7.07 (m, 4H, ArH); C NMR (100 MHz,
The H NMR spectra of chiral calix [4] arene deriva-
2
2
CDCl ): δ=21.0, 29.4, 30.4, 42.4, 70.8, 78.3, 127.8, 130.0,
tives exhibit two sets of doublets 3.34 ppm (J = 13.0 Hz)
and 4.03 ppm (J = 13.2 Hz) for 2a–b and 3.33 ppm
(J = 13.2 Hz) and 4.41 ppm (J = 13.6 Hz) for 3a–b due to
the bridging methylene protons. This indicates that chiral
calix [4] arene derivatives adopt a cone conformation in
3
1
32.8, 138.3, 201.1, 201.9; The enantiomeric excess was
determined by HPLC (Chiralcel AD-H), Hexane: i-PrOH
9
1
0:10, UV 210 nm, flow rate 0.8 mL/min, R-isomer, t
R
6.98 min and S-isomer, t 10.64 min. 77% ee.
R
CHCl .
3
(
S)‑3‑[1‑(4‑Chlorophenyl)‑2‑nitroethyl]pentane‑2,4‑di‑
The catalytic activity of these calixarene thiourea organo-
catalysts was initially evaluated in the conjugate addition
reaction of acetylacetone (5) to trans-β-nitrostyrene 4a in
the presence of 10 mol% of catalyst 2a at room tempera-
ture. To check the effect of various solvents for better yield
and selectivities, the same reaction was tested in different
solvents and the results were summarized in Table 1. Ten
different solvents with organocatalyst 2a were examined
to find optimum reaction media and the conjugate addition
one (6i)
This compound was obtained from 4-Cl-β-nitrostyrene and
acetylacetone to provide the title compound (91% yield)
and purified by flash chromatography (petroleum ether/
2
5
−1
ethyl acetate=5:1). α : +19.2 (c=0.5, CHCl ); IR (cm ):
D
3
8
21, 1141, 1270, 1361, 1332, 1732, 1482, 1549, 1701;
1
H NMR (400 MHz, CDCl ): δ = 1.91 (s, 3H, COCH ),
3
3
2
4
.23 (s, 3H, COCH ), 4.19–4.13 (m, 1H, ArCHCH ),
reaction with organocatalyst 2a in CH CN afforded the best
3
2
3
.27 (d, J = 10.5 Hz, 1H, COCHCO), 4.55–4.53 (m, 2H,
enantioselectivity (81% ee; Table 1, Entry 7).
CHCH NO ), 7.08–7.06 (m, 2H, ArH), 7.26–7.23 (m, 2H,
Solvent evaluation revealed that both the yield and the
enantioselectivity were highly dependent on the solvent.
Polar solvents such as 1,1-dichloroethane, EtOAc and
2
2
1
3
ArH); C NMR (100 MHz, CDCl ): δ = 29.7, 30.5, 42.1,
3
7
0.5, 77.9, 129.3, 129.6, 134.5, 200.6, 201.4; The enantio-
meric excess was determined by HPLC (Chiralcel AS-H),
Hexane: i-PrOH 85:15, UV 210 nm, flow rate 1 mL/min,
R-isomer, t 31.46 min and S-isomer, t 15.24 min. 88% ee.
CH CN gave higher yields and enantioselectivities (Table 1,
3
entries 4, 5 and 7). When a nonpolar solvent such as tolu-
ene and CCl were used, both the yield and enantioselectiv-
R
R
4
ity decreased remarkably (Table 1, entries 2 and 6). After
(
R)‑3‑[1‑(2,4‑Dichlorophenyl)‑2‑nitroethyl]pen‑
selecting CH CN as the most efficient solvent, we proceeded
3
tane‑2,4‑dione (6j)
to investigate the influence of different experimental param-
eters including temperature and catalyst loading in the asym-
metric Michael addition reaction. The results were also sum-
marized in Table 1, entries 11 and 12. In order to evaluate
the efficiency of chiral bifunctional organocatalyst 2a in the
Michael addition of acetylacetone to trans- β -nitrostyrene,
different catalyst loading (15 mol%) was also tested. Increas-
ing of catalyst loading from 10 to 15% led to some loss in
enantioselectivity and yield (Table 1, entry 11). In addition
0 °C showed less desired yields and enantioselectivities than
the reaction at room temperature (Table 1, entry 12).
This compound was obtained from 2,4-Cl-β-nitrostyrene and
acetylacetone to provide the title compound (93% yield) and
purified by flash chromatography (petroleum ether/ethyl ace-
2
5
−1
tate=5:1). α : +59.1 (c=2.25, CHCl ); IR (cm ): 1360,
D
3
1
1
378, 1475, 1550, 1704, 1730; H NMR (400 MHz, CDCl ):
3
δ = 2.06 (s, 3H, COCH ), 2.29 (s, 3H, COCH ), 4.54 (d,
3
3
J=9.7 Hz, 1H, COCHCO), 4.71–4.61 (m, 2H, CHCH NO ),
2
2
4
.84–4.80 (m, 1H, ArCHCH ), 7.10 (d, J = 8.4 Hz, 1H,
2
ArH), 7.24–7.21 (m, 1H, ArH), 7.45 (d, J = 2.1 Hz, 1H,
1
3
ArH); C NMR (100 MHz, CDCl ): δ = 28.6, 30.9, 38.4,
The influence of additives was also studied in an attempt
to improve the turnover frequency of the catalyst by accel-
erating the rate of formation of the intermediate enamine. A
survey of several acids including benzoic acid, acetic acid
and trifluoroacetic acid did not improve catalyst efficiency
and in some cases both the yield and selectivity decreased.
3
6
8.8, 76.0, 128.0, 130.5, 132.1, 134.5, 135.1, 200.5, 201.6;
The enantiomeric excess was determined by HPLC (Chiral-
cel AD-H), Hexane: i-PrOH 90:10, UV 210 nm, flow rate
1
8
mL/min, R-isomer, t 12.21 min and S-isomer, t 9.68 min.
R
R
6% ee.
(
-
Table 2, entries 2, 5 and 9). Also when using (R-) or (S-)
1,1′-bi-2- naphthol, pyridine and quinine as additives, both
Results and discussion
yields and ee values were inferior. (Table 2, entries 3, 4, 6
and 7). The catalytic reactivity of 2a was examined for the
Michael addition of acetylacetone to trans-β-nitrostyrene, in
Bifunctional calixarene thiourea organocatalysts (1R, 2R)-
a, (1S, 2S)-2b, (1R, 2R)-3a and (1S, 2S)-3b were synthe-
sized from the reaction of primary amine-thioureas 1a and
2
CH CN without an additive could be the optimal reaction
3
conditions.
1
3

J Incl Phenom Macrocycl Chem
Ph
Ph
PhPh
(
H
2
C)
3
(CH2)3
N
N
NH2
H N
2
N
N
*
*
*
*
*
*
*
*
*
*
*
(CH
)
3
(CH
2
2
)
3
*
NH
NH
HN
HN
NH
NH
HN
HN
NH
NH
HN
S
S
S
S
S
S
HN
CH CH CHO
3
2
Ph CH 2CHO
2
( )
NaBH CN
3
K CO
2
3
O
HO OH
O
O
HO OH
O
O
HO OH
O
AcOH, CH CN
CH
3
CN
3
2
a-2b
1a-1b
3a-3b
Ph
Ph
PhPh
Ph
Ph
(
H
C)
(CH2)3
N
(H
C)
2
3
2
3
(CH2)3
N
N
N
N
N
N
N
PhPh
(
CH
2
)
3
(CH
(CH
(CH
)
2
3
2
)
3
2
)
3
NH
NH
HN
HN
NH
NH
HN
HN
NH
NH
HN
NH
NH
HN
S
S
S
S
S
S
S
S
HN
HN
O
HO OH
O
O
HO OH
O
O
HO OH
O
O
HO OH
O
2
a
2b
3a
3b
Scheme 1 Chiral calix [4] arene thiourea catalysts 2a/2b and 3a/3b
Chiral p-tert-butylphenol analogue 11 was synthesized
to confirm the role of the achiral calixarene backbone
from the chiral primary amine–thiourea 10. Primary
amine 10 was synthesized starting from p-tert-butyl phe-
nol in four steps and 68% overall yield according to the
known procedure [25] as described in Scheme 2. Then it
was reacted with propionaldehyde and sodium cyanoboro-
interesting to note that the presence of bulky calixarene
moiety of thiourea and the phenolic hydroxy groups on the
calixarene scaffold as acidic additives plays a crucial role
in helping to increase the electrophilicity of nitrostyrene
and preorganising the reaction substrates. It was realized
that the aliphatic calix [4] arene-based thiourea 2a was
found to be the best choice for this doubly stereocontrolled
organocatalytic process.
hydride in CH CN to obtain the chiral p-tert-butylphenol
3
analogue 11.
Through extensive screening, the optimized reaction
conditions of the Michael addition of acetylacetone to
nitroolefins were set up (catalyst 2a, acetonitrile as sol-
vent, room temperature). The doubly stereocontrolled
asymmetric addition of 2,4-pentanedione to a variety of
nitroalkenes was examined considering the usefulness
and versatility of adducts in organic synthesis. A variety
of aryl nitroolefins (4a–j) reacted smoothly with acety-
lacetone (5) to afford the corresponding products (6a–j)
in high yields (up to 97%) and excellent enantioselectivi-
ties (up to 92% ee) in the presence of 10 mol% of catalyst
2a at room temperature within 8–24 h. It was seen that
all reactions of aromatic nitroalkenes proceed smoothly
affording the desired products of the (S) or (R) configura-
tion with high to excellent enantioselectivities (Table 4,
(R)-adducts, 77–92%, entries 5, 7, 8, 10 and (S)-adducts,
81–90%, entries 1–4, 6, 9) and yields. It appears that
Both aliphatic and aromatic calix [4] arene-based thio-
ureas 2a–2b and 3a–3b catalyze the Michael addition reac-
tion of acetylacetone to trans-β-nitrostyrene in CH CN
3
high enantioselectivities of up to 81% ee (Table 3). Dif-
ferent catalysts also led to different enantioexcess value.
Catalyst (1R, 2R)-2a, was also superior to other tested cata-
lysts, such as 2b, 3a, 3b and 9 (Table 3, entry 1), resulting
in both excellent yield and enantioselectivity. (1S, 2S)-2b
(
10 mol%) was screened as catalyst at room temperature
the product was obtained in 86% yield and 79% ee (Table 3,
entry 3). When using aromatic calix [4] arene-based thiou-
reas 3a and 3b as catalyst, the enantioselectivity decreased
dramatically and down to 73 and 72% (Table 3, entries 2
and 4). Chiral p-tert-butylphenol analogue 11 was tested as
catalyst in Table 3, entry 5. When using 11 as catalyst, both
yield and ee value were inferior (yield 85%, ee %51). It is
1
3

J Incl Phenom Macrocycl Chem
Table 1 Optimization of reaction conditions for asymmetric Michael addition reactions between acetylacetone (5) and trans-β-nitrostyrene (4a)
Entrya
Catalyst
Solvent
CH Cl
Toluene
Time (h)
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
8
8
4
24
24
24
24
24
6
92
94
89
95
93
94
97
90
78
65
92
83
72 (S)
73 (S)
70 (S)
76 (S)
78 (S)
69 (S)
81 (S)
72 (S)
52 (S)
63 (S)
80 (S)
76 (S)
2
2
CHCl3
ClCH CH Cl
2
2
EtOAc
CCl4
CH CN
3
THF
MeOH
DMF
10
11
12
6
24
24
e
f
CH CN
3
CH CN
3
a
All reactions were carried out with trans-β-nitrostyrene (0.05 mmol), acetylacetone (0.1 mmol) and the catalyst indicated (10 mol%) in solvents
(
0.125 mL)
b
Yield of the isolated product after column chromatography
Analyzed in HPLC with chiral AS-H column
The configuration was assigned by comparison of the retention time and specific rotation with literature data
We employed 15 mol% of catalyst
c
d
e
f
Reaction was carried in an ice bath
the position and the electronic property of the substit-
uents for aromatic rings of nitroalkenes 4a–j are well
tolerated by the enantioselective conjugate addition reac-
tions. Whether electron-withdrawing (Table 4, entries 4,
presence of 2a as a catalyst proposed [32]. First, thio-
urea moieties of the catalyst 2a was assumed to inter-
act through hydrogen bonding with a nitro group of the
nitroolefins while the tertiary amine deprotonates an
acidic proton of acetylacetone, generating a ternary com-
plex, meanwhile the hydroxyl group of the calix [4] arene
and the nitro group may form another hydrogen bond,
which enhances the electrophilicity of the nitroolefins.
Steric hindrance from both moieties (calixarene moiety
and the thiourea moiety) of the chiral bifunctional cata-
lyst 2a and the nuclephilic attack on the re-face of nitros-
tyrene might be helpful for the increased stereocontrol of
the Michael addition reaction.
7
and 9), electrondonating (Table 4, entries 6 and 8), or
electron-neutral (Table 4, entry 1) groups on aromatic
rings were used, the reactions proceeded smoothly to
give the desired adducts in good yields (81–97%) with
good enantioselectivity (77–88% ee). While substitution
of the 2-Br-β-nitrostyrene at the ortho position was well
tolerated, meta and para substitutions resulted in a loss
of enantioselectivity (Table 4, entries 2–4). More signifi-
cant example was the reaction of 2-MeO-β-nitrostyrene
(
4e) which offer Michael product in much higher enan-
Surprisingly, the Michael addition of acetylacetone to
nitroolefins in the presence of 2a also led to the opposite
asymmetric induction with high yields and enantioselec-
tivities (Table 4, entries 5, 7, 8, 10) under the same condi-
tions because of the nuclephilic attack on the opposite-face
of nitrostyrene. This selectivity is the reverse of that nor-
mally found for this example in literatüre [33–35].
tiomeric excesses up to 92% ee.
Although the precise reaction mechanism needs fur-
ther study, a possible transition state has been proposed
based onthe observed stereoselectivities of the asym-
metric Michael addition of acetylacetone to nitroolefins.
A plausible catalytic mode representing the Michael
addition of acetylacetone 5 to nitroolefins 4a–j in the
1
3

J Incl Phenom Macrocycl Chem
Table 2 Screening of additives for 2a catalyzed addition of acetylacetone (5) to trans-β-nitrostyrene (4a)
Entrya
Additive (10 mol%)
Time (h)
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
Et N
6
48
24
24
64
36
36
48
48
96
92
85
88
83
78
81
79
80
76
<1
78 (S)
75 (S)
74(S)
76 (S)
63 (S)
79 (S)
78 (S)
75 (S)
73 (S)
n.d.e
3
Benzoic acid
(S-)-1,1′-Bi-2-Naphthol
(R-)-1,1′-Bi-2- Naphthol
AcOH
Pyridine
Quinine
p-TsOH
TFA
DMAP
1
0
a
All reactions were carried out with trans-β -nitrostyrene (0.05 mmol), acetylacetone (0.1 mmol) and the catalyst indicated (10 mol%) in CH CN
3
(
0.125 mL)
b
Yield of the isolated product after column chromatography
Analyzed in HPLC with chiral AS-H column
The configuration was assigned by comparison of the retention time and specific rotation with literature data
Not determined
c
d
e
Scheme 2 Synthesis of chiral
p-tert-butylphenol analogue 11
O
N
NH
2
N
O
NH
NH
NH
S
S
S
NH2
NH
NH
NH
O
SCN
N
O
O
O
O
O
CH
CH CHO
2
3
N H .H O
NaBH CN
7
2
4
2
3
CH
Cl
EtOH
AcOH, CH CN
3
2
2
8
10
11
9
Conclusion
of dicarbonyl compounds to nitroolefins as a model we
have tested the ability of these structures as enantioselec-
tive organocatalysts, proving the generality of their use.
Among the tested catalysts, 2a, was the most promising
in yield and enantioselectivity. In optimal conditions,
In conclusion, a new class of bifunctional calixarene thio-
urea organocatalysts bearing multiple hydrogen bonding
donors was synthesized and taking the Michael addition
1
3

J Incl Phenom Macrocycl Chem
Table 3 Screening of different catalyst in the asymmetric Michael addition reactions between acetylacetone (5) and trans-β-nitrostyrene (4a)
Entrya
Catalyst
Time (h)
Yield (%)b
ee (%)c,d
1
2
3
4
5
2a
3a
2b
3b
11
24
36
24
36
24
97
80
86
82
85
81 (S)
73 (S)
79 (S)
72 (S)
51 (S)
a
All reactions were carried out with trans-β -nitrostyrene (0.05 mmol), acetylacetone (0.1 mmol) and the catalyst indicated (10 mol%) in CH CN
3
(
0.125 mL)
b
Yield of the isolated product after column chromatography
Analyzed in HPLC with chiral AS-H column
The configuration was assigned by comparison of the retention time and specific rotation with literature data
c
d
Table 4 Asymmetric Michael addition reactions between acetylacetone and different nitroolefins
Entrya
R
Time (h)
Product
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
C H
2-Br-C H
3-Br-C H
4-Br-C H
2-MeO-C H
4-MeO-C H
4-F-C H
4-Me-C H
24
24
12
12
24
24
8
24
8
8
6a
6b
6c
6d
6e
6f
97
65
72
81
93
95
85
89
91
93
81 (S)
90 (S)
83 (S)
83(S)
92 (R)
82 (S)
79 (R)
77 (R)
88 (S)
86 (R)
6
5
6
4
4
4
6
6
6
4
4
6
6g
6h
6i
6
4
6
4
4-Cl-C H
2,4-Cl-C H
6
4
1
0
6j
6
3
a
All reactions were carried out with trans-β -nitrostyrene (0.05 mmol), acetylacetone (0.1 mmol) and the catalyst 2a (10 mol%) in CH CN
3
(
0.125 mL)
b
Yield of the isolated product after column chromatography
Analyzed in HPLC with chiral AS-H and AD-H columns
The configuration was assigned by comparison of the retention time and specific rotation with literature data
c
d
1
3

J Incl Phenom Macrocycl Chem
organocatalyst 2a promoted the asymmetric conjugate
addition of acetylacetone to various nitroolefins at room
temperature in good yields (up to 97%) and with good
enantioselectivity (up to 92% ee). Further investigation
of these organocatalysts in other asymmetric reactions as
well as a more detailed mechanism is currently on going
in our laboratory.
for enantioselective synthesis of α-amino acids. Tetrahedron 19,
6
18–623 (2008)
1
1
4. Luo, J., Zheng, Q.Y., Chen, C.F., Huang, Z.T.: Facile synthesis
and optical resolution of inherently chiral fluorescent calix[4]
crowns: enantioselective recognition towards chiral leucinol.
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Acknowledgements The authors gratefully acknowledge the finan-
cial support of this work given by the Scientific and Technological
Research Council of Turkey (TUBITAK-113Z696) and Research Foun-
dation of Necmettin Erbakan University (BAP-141110003).
16. Xu, H., Kinsel, G.R., Zhang, J., Li, M., Rudkevich, D.M.: Calix-
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Lemaire, M.: Synthesis of new calix[4]arene based chiral ligands
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