Calixarene-based highly efficient primary amine-thiourea organocatalysts for asymmetric Michael addition of aldehydes to nitrostyrenes

Article abstract of DOI:10.1080/10610278.2013.773331

The synthesis of calix[4]arene-based chiral bifunctional primary amine-thiourea catalysts has been described from p-tert-butylcalix[4]arene for the first time. The calix[4]arene-based catalysts were successfully applied to promote Michael addition of alde

Full text of DOI:10.1080/10610278.2013.773331

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Calixarene-based highly efficient primary
amine–thiourea organocatalysts for asymmetric
Michael addition of aldehydes to nitrostyrenes
Mustafa Durmaz a & Abdulkadir Sirit a
a Department of Chemistry, Necmettin Erbakan University, Meram, Konya, 42099, Turkey
Published online: 04 Mar 2013.
To cite this article: Mustafa Durmaz & Abdulkadir Sirit (2013) Calixarene-based highly efficient primary amine–thiourea
organocatalysts for asymmetric Michael addition of aldehydes to nitrostyrenes, Supramolecular Chemistry, 25:5, 292-301,
DOI: 10.1080/10610278.2013.773331
To link to this article: http://dx.doi.org/10.1080/10610278.2013.773331
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Supramolecular Chemistry, 2013
Vol. 25, No. 5, 292–301, http://dx.doi.org/10.1080/10610278.2013.773331
Calixarene-based highly efficient primary amine–thiourea organocatalysts for asymmetric
Michael addition of aldehydes to nitrostyrenes
Mustafa Durmaz and Abdulkadir Sirit*
Department of Chemistry, Necmettin Erbakan University, Meram, Konya 42099, Turkey
(Received 27 November 2012; final version received 29 January 2013)
The synthesis of calix[4]arene-based chiral bifunctional primary amine–thiourea catalysts has been described from p-tert-
butylcalix[4]arene for the first time. The calix[4]arene-based catalysts were successfully applied to promote Michael
addition of aldehydes with nitroalkenes affording preferentially the (R)- or (S)-adducts in high yields (up to 95%) and
excellent enantioselectivities (up to 99% ees).
Keywords: calixarenes; asymmetric catalysis; Michael addition; nitroolefins; organocatalysis
1. Introduction
organocatalysts (12), ionophores in catalysis, carriers in
liquid membrane technology, extractants for anions and
cations and chemical sensors (13).
Asymmetric organocatalysis, using enantiomerically pure
organic compounds, has emerged as a convenient and
highly useful method during past decade and is now
appreciated as the third branch in asymmetric catalysis
together with enzymatic and organometallic catalysis (1).
Michael addition reaction is among the most powerful
and versatile methods for the formation of CZC bonds in
organic synthesis (2). In particular, the asymmetric
conjugate addition of a carbon nucleophile to a nitroalkene
is a challenging task (3). Since Barbas and co-workers first
reported the asymmetric Michael addition of ketones to
alkylidene malonates (4) and of aldehydes to nitrostyrene
(5) catalysed by diamines containing a pyrrolidine moiety,
interest in the field of asymmetric Michael addition has
increased intensively and a variety of effective organoca-
talysts have been developed (6). Among them, chiral
bifunctional amine–thioureas have been proven as
effective catalysts and have been applied successfully in
asymmetric catalytic Michael addition reactions, i.e. by
Jacobsen (7), Barbas (8), Chen (9) and others (10). Despite
these elegant works, the development of a new type of
organocatalyst and search for new nucleophiles remain a
worthwhile and desirable endeavour.
To the best of our knowledge, the use of calixarene
derivatives has not been reported as effective chiral
catalysts in organocatalytic Michael reactions. However,
the preparation of both enantiomers of a chiral compound
with high enantioselectivity is an important challenge in
the pharmaceutical industry and is a highly desirable goal
in organic synthesis (14), but only a few organocatalysts
have previously been reported to prepare both enantiomers
of adducts selectively through organocatalytic Michael
additions between aldehydes and nitroalkenes (15).
As part of our programme aimed at developing new
chiral receptors equipped with various functionalities as
well as their catalytic activities (16), transport abilities
(17) and enantiomeric recognition properties (18) herein,
we report the design and synthesis of a novel class of
calix[4]arene-based chiral primary amine–thioureas in
both enantiomeric forms, which are very effective
bifunctional organocatalysts for highly enantioselective
Michael addition of aldehydes to nitroalkenes.
2. Results and discussion
Calixarenes are phenol-based macrocycles (11), and
represent a versatile class of macrocyclic compounds due
to their potential for forming host–guest complexes with
numerous classes of compounds in supramolecular
chemistry. Chirality in calixarenes can be generated by
either attaching chiral substituents at one of the rims
(lower or upper) or synthesising ‘inherently’ chiral
derivatives, in which the non-planarity of the molecule is
exploited. Chiral receptors that are based on the calixarene
platform may have potential applications, such as
A multistep route for preparing the chiral calix[4]arene
derivatives bearing primary amine–thiourea moieties is
shown in Scheme 1. Thus, following the literature
procedures (9,19), chiral isothiocyanates 2a and 2b were
readily prepared from trans-1,2-diaminocyclohexane in
two steps with good overall yields. The chiral calix[4]-
arene derivatives 4a and 4b were obtained in 84% and 82%
yields by the reaction of p-tert-butylcalix[4]arene diamine
1a (20) with chiral subunits 2a and 2b and subsequent
*Corresponding author. Email: asirit42@yahoo.com
q 2013 Taylor & Francis

Supramolecular Chemistry
293
NH
H N
2
2
O
O
H N
2
N
N
NCS
NCS
O
O
O
O
O
OH OH
2a
2b
dry CH Cl
2
dry CH Cl
2
2
2
rt, 24h
rt, 24h
1b
dry CH Cl
2
1a
2
O
O
O
O
O
N
NCS
rt, 24h
N
N
O
N
N
O
O
O
O
2b
NH
NH
NH
NH
HN
HN
HN
HN
S
S
S
S
O
N
O
HN
O
O
O
O
OH OH
OH
OH
S
HN
O
3a
3b
N H .H O
3c
N H .H O
N H .H O
2
4
2
2
4
2
EtOH
reflux
EtOH
reflux
2
4
2
EtOH
reflux
NH
2
H N
2
NH
H N
2
2
NH
NH
HN
HN
NH
NH
HN
HN
H N
2
S
S
S
S
HN
HN
S
O
O
O
O
OH OH
OH OH
O
4c
4a
4b
Scheme 1. Synthesis of chiral calix[4]arene–thiourea catalysts 4a/4b and p-tert-butylphenol analogue 4c.
cleavage of chiral phthalimides 3a and 3b with hydrazine
hydrate by refluxing in ethanol.
Encouraged by this result, we continued our research
to obtain higher yield and enantioselectivity by the
optimisation of reaction conditions. The effect of additives
was also taken into consideration. Some typical acids,
bases and water were surveyed in CH2Cl2, and the data are
given in Table 1. It is interesting to note that the chemical
yields and stereoselectivities were changed to different
extents, depending on the nature of the additive used. In
each case, the reactions proceeded very slowly in the
presence of additives and the resulting chemical yields and
enantioselectivities were significantly decreased after 96 h
(Table 1, entries 12–20).
With these novel catalysts in hand, we then investigated
the effects of the calix[4]arene-based catalysts for the
enantioselective Michael addition of isobutyraldehyde
with b-nitrostyrenes. To evaluate the catalytic efficiency of
calix[4]arene-based chiral catalysts, the addition of
isobutyraldehyde to b-nitrostyrene was carried out in
various solvents in the presence of each of these catalysts
(Table 1, entries 1–11) at room temperature (rt).
Initial screening studies indicated that isobutyralde-
hyde could react with nitrostyrene in the presence of
calix[4]arene 4a and 4b (15 mol %) in CH2Cl2 at rt for 30–
32 h to afford the desired product in excellent yields with
good to excellent enantioselectivities (90–98% ees) in
both enantiomeric forms (Table 1, entries 1 and 2).
Furthermore, the use of CHCl3, toluene, CCl4 and 1,2-
DCE as solvents slightly decreased the reactivity and
enantioselectivity (Table 1, entries 3–8), whereas using
DMSO or i-PrOH only afforded a trace of product (Table 1,
entries 9–11). CH2Cl2, thus, remained the solvent of choice.
Having identified the best solvent and reaction medium,
we next probed the effect of catalyst loading onthe reaction.
Catalyst loadings, ranging from 10 to 2 mol %, were
evaluated. Excellent chemical yields, without compromise
to the enantioselectivity of the reaction, were obtained
using catalyst loadings of 10 mol % (Table 1, entry 21).
Remarkably lowering the amount of catalyst to 5 and
2 mol % showed a significant decrease in enantioselectivity

294
M. Durmaz and A. Sirit
CH2Cl2 using 15 mol % of the chiral calix[4]arene
derivatives 4a and 4b at rt.
Table 1. Optimisation of the asymmetric Michael addition of
isobutyraldehyde to trans-b-nitrostyrene catalysed by 4a–4ca.
As summarised in Table 3, the reaction of cyclopenta-
necarboxaldehyde with various b-nitrostyrenes afforded
the desired products 5 m/5 m0 –5u/5u0 in 70–89% isolated
yields with 87–99% ees. However, decreasing the catalyst
loading to 10 mol % reduced the reaction rate along with a
loss of enantiomeric excess. Moreover, employment of 5
and 2 mol % of catalyst 4 only gave trace amounts of
product 5 m/5 m0 after 24 h. The results in Table 3 also
indicate that the position and the electronic property of the
substituents on the aromatic rings of nitroalkenes had a
limited influence on the stereoselectivity of conjugate
additions.
O
O
NO2
Catalyst (15 mol%)
*
NO2
+
H
H
solvent, rt
5a/5a'
Additive
(15 mol %) t/h
Yield
(%)b
ee
(%)c,d
Entry Cat.
Solvent
1
2
3
4
5
6
7
8
4a
4b
4a
4b
4a
4b
4b
4b
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4c
4c
4c
CH2Cl2
CH2Cl2
CHCl3
–
–
–
–
–
–
–
–
30
32
36
36
36
36
48
36
48
48
48
96
96
96
96
96
96
96
96
96
36
96
96
60
60
60
89
93
92
90
85
88
76
89
,5
,5
,5
17
,5
61
60
32
83
72
47
76
91
45
20
52
56
60
90 (R)
98 (S)
87 (R)
96 (S)
88 (R)
97 (S)
97 (S)
97 (S)
n.d
n.d.
n.d.
97 (S)
n.d.
67 (S)
59 (S)
87 (S)
97 (S)
51 (S)
83 (S)
95 (S)
98 (S)
95 (S)
70 (S)
89 (S)
87 (S)
86 (S)
CHCl3
In order to confirm the role of the achiral calixarene
platform of 4a and 4b, a key control reaction was carried
out because more simple primary amine–thioureas are
known to be good catalysts for the asymmetric Michael
addition of aldehydes to nitroalkenes. The chiral primary
amine–thiourea 4c was synthesised starting from p-tert-
butyl phenol in four steps and 68% overall yield by the
same procedure as described in Scheme 1 and tested as
catalyst. The enantioselective Michael addition of
isobutyraldehyde with b-nitrostyrene in CH2Cl2, CHCl3
and toluene for 60 h afforded the (S) Michael product in
lower yields (52–60%) and enantioselectivities (86–89%
Table 1, entries 24–26) than the calixarene-based chiral
primary amine–thiourea derivatives. These results showed
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 pre-
organising the reaction substrates.
Toluene
Toluene
CCl4
1,2-DCE
DMSO
DMSO
i-PrOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
9
–
–
10
11
12
13
14
15
16
17
18
19
20
21e
22f
23g
24
25
26
–
AcOH
PhCOOH
DMAP
DABCO
Et3N
Pyridine
DIPEA
TBABr
H2O
–
–
–
–
–
Toluene
–
Based on the observed stereoselectivities of Michael
addition of isobutyraldehyde to nitroalkenes, a possible
transition state was proposed. As outlined in Figure 1, the
primary amino group of 4a or 4b condenses with the
aldehyde to generate the enamine intermediate, whereas
the acidic protons of the thiourea group of catalyst interact
through hydrogen bonding with a nitro group of the
nitroalkene and control the direction of approach of the
nitroalkenes to the enamine intermediate. The attack of
this enamine from the re- or si-face of the nitrostyrene
leads to the formation of addition products 5 with (R)- or
(S)-configuration.
Note: n.d., Not determined.
a All reactions were carried out with isobutyraldehyde (3 equiv.), trans-b-
nitrostyrene (1 equiv.) and the catalyst indicated (15 mol %) in solvents
(1.0 mL).
b Isolated yield.
c Determined by chiral HPLC analysis (Chiralcel OD-H).
d The absolute configuration was determined by comparison with
literature data.
e 10 mol % catalyst was used.
f 5 mol % catalyst was used.
g 2 mol % catalyst was used.
with some loss in yield (Table 1, entries 22 vs. 23) and
extended reaction times were required.
To examine the scope and limitations of the reaction, a
wide range of b-nitrostyrene derivatives efficiently reacted
with isobutyraldehyde under optimised conditions to give
the Michael adducts in both enantiomeric forms. As given
in Table 2, the introduction of various electron with-
drawing and electron donating groups on the aromatic ring
of the nitroalkenes slightly affected enantioselectivities
(84–98% ee) and yields (79–95%). In order to expand the
generality of this catalytic system, we further varied the
Michael donor in Michael additions to b-nitrostyrene in
3. Experimental
3.1 General
Melting points were determined on an Electrothermal
1
9100 apparatus in a sealed capillary. H and 13C NMR
spectra were recorded in CDCl3 at rt on Varian 400 and
Bruker 400 instruments. Chemical shifts are reported in
ppm. Data are reported as follows: chemical shift (ppm),

Supramolecular Chemistry
295
a
Table 2. Substrate studies of Michael additions of isobutyraldehyde to the various nitroalkenes under optimised conditions in CH2Cl2 .
O
R
Catalyst 4a (10 mol%)
NO2
H
H
O
CH2Cl2, rt
5b –51
NO2
+
H
R
O
R
Catalyst 4b (10 mol%)
NO2
CH2Cl2, rt
5b –51
Entry
R
Adduct
t/h
Yield (%)bR/S
ee (%)c R/S
1
2
3
4
5
6
7
8
4-F-C6H4
4-Cl-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
2-NO2-C6H4
2-furyl
5b/5b0
5c/5c0
5d/5d0
5e/5e0
5f/5f0
24/30
40/48
48/60
48/48
20/24
36/36
36/36
30/36
40/48
32/40
30/36
85/81
89/84
82/78
79/76
91/87
82/80
80/76
95/92
81/77
82/84
84/79
92/98
91/98
94/96
90/92
91/97
84/95
89/88
90/94
90/95
89/97
89/94
5 g/5g0
5 h/5 h0
5i/5i0
4-CH3-C6H4
9
10
11
2-CH3O-C6H4
3-CH3O -C6H4
4-CH3O-C6H4
5j/5j0
5k/5k0
5 l/5l0
a All reactions were carried out with isobutyraldehyde (3 equiv.), nitroalkene (1 equiv.) and the catalyst indicated (10 mol %) in CH2Cl2 (1.0 mL).
b Isolated yield.
c Determined by chiral HPLC analysis.
multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet;
br, broad) and coupling constants (Hz). Infrared (IR)
spectra were recorded on a Perkin Elmer spectrum-100
FT-IR spectrometer equipped with an Attenuation Total
Reflection (ATR) unit and are reported in wavenumbers
(cm21). The high-pressure liquid chromatography (HPLC)
measurements were carried out on Agilent 1100 equip-
ment connected with Chiralpak Daicel AD-H and OD-H
columns. Optical rotations were measured on an Atago
AP-100 digital polarimeter using a 1 dm cell. Elemental
analyses were carried out using a Leco CHNS-932
analyser. Analytical thin layer chromatography (TLC) was
carried out using Merck prepared plates (silica gel 60 F254
on aluminium). Flash chromatography separations were
Table 3. Substrate studies of Michael additions of cyclopentanecarboxaldehyde to the various nitroalkenes under optimised conditions
in CH2Cl2 .
a
O
R
NO2
H
H
Catalyst 4a (15 mol%)
O
CH2Cl2, rt
NO2
5m –5u
R
H
+
R
O
Catalyst 4b (15 mol%)
NO2
CH2Cl2, rt
5m –5u
Entry
R
Adduct
t/d
4/4
4.5/4.5
5/5
3.5/3
4.5/4
3/2.5
3/3
3/3
2.5/2
Yield (%)bR/S
ee (%)c R/S
1
2
3
4
5
6
7
8
9
C6H5
5 m/5 m0
5n/5n0
5o/5o0
5p/5p0
5q/5q0
5r/5r0
5s/5s0
71/76
75/77
70/71
72/79
76/84
79/81
75/82
82/86
84/89
88/93
90/94
92/96
90/96
90/95
90/94
90/95
87/94
90/99
4-CH3-C6H4
2-CH3O-C6H4
3-CH3O-C6H4
4-CH3O-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
4-Cl-C6H4
5t/5t0
5u/5u0
a All reactions were carried out with cyclopentanecarboxaldehyde (3 equiv.), nitroalkene (1 equiv.) and the catalyst indicated (15 mol %) in CH2Cl2
(1.0 mL).
b Isolated yield.
c Determined by chiral HPLC analysis.

296
M. Durmaz and A. Sirit
Figure 1. Proposed transition state model of Michael addition.
carried out on a Merck Silica Gel 60 (230–400 mesh). All
starting materials and reagents used were of standard
analytical grade from Fluka, Merck and Aldrich and were
used without further purification. Dichloromethane was
dried (CaCl2), distilled from CaH2 and stored over
molecular sieves. Other commercial grade solvents were
distilled, and then stored over molecular sieves. The
drying agent used was anhydrous MgSO4.
3.2.2 Chiral phthalimide 3c
25
Amorphous solid, 0.432 g, 90% yield. ½aꢀD 22.07 (c 0.6,
CHCl3). IR (cm21): 3341, 3062, 2937, 2862, 1768, 1698,
1610, 1547, 1512, 1467, 1390, 1371, 1294, 1243, 1183,
1150, 1101, 1088, 1047, 905, 869, 828, 751, 716, 662. 1H
NMR (400 MHz, CDCl3): d ¼ 7.61 (br s, 2H), 7.57–7.53
(m, 2H), 7.27–7.23 (m, 2H), 6.75 (d, J ¼ 8.3 Hz, 2H), 6.37
(t, J ¼ 5.5 Hz, 1H), 6.26 (d, J ¼ 9.7 Hz, 1H), 4.74 (br s,
2H), 4.04–3.97 (m, 1H), 3.90–3.87 (m, 2H), 3.82–3.60
(m, 2H), 2.58–2.18 (m, 2H), 1.90–1.74 (m, 3H), 1.55–
1.40 (s, 1H), 1.39–1.11 (m, 10H). 13C NMR (100 MHz,
CDCl3): d ¼ 182.1, 168.9, 155.9, 143.9, 133.9, 131.6,
126.2, 123.2, 114.0, 66.7, 54.9, 34.1, 33.2, 31.5, 28.9, 25.3,
24.5. Anal. Calcd. for C27H33N3O3S (479.63): C, 67.61; H,
6.93; N, 8.76%. Found: C, 67.69; H, 6.84; N, 8.69%.
3.2 General procedure for the synthesis of 3a–3c
To a solution of 2a or 2b (0.172 g, 0.6 mmol) in dry
CH2Cl2 (10 mL) was added p-tert-butylcalix[4]arene
diamine 1a (0.23 g, 0.3 mmol) or 2-(4-tert-butylphenox-
y)ethanamine 1b (21) (0.116 g, 0.6 mmol). The reaction
mixture was stirred for 24 h at rt. After removal of solvent,
the crude product was purified by flash chromatography
(hexane–EtOAc) to afford 3a–3c.
3.3 General procedure for the synthesis of chiral
calix[4]arene-based primary amine–thioureas 4a and 4b
Theprotectedthiourea–amine3aor3b(0.30 g,0.236 mmol)
and hydrazine hydrate (0.3mL, 85% in H2O) were dissolved
in EtOH (5mL) and refluxed for 2 h. The mixturewas cooled
to rt and the solvent was then removed under vacuum. The
residue was dissolved in CHCl3 (10 mL), washed with water
(2 £ 10mL), dried (MgSO4) and purified by flash chroma-
tography on silica gel (CHCl3–MeOH) to give 4a or 4b.
3.2.1 Chiral phthalimides 3a and 3b
Chiral phthalimide 3a. Amorphous solid, 0.347 g, 91%
25
yield. ½aꢀD þ 2.46 (c 0.8, CHCl3). Chiral phthalimide 3b.
25
Amorphous solid, 0.353 g, 88% yield. ½aꢀD 22.74 (c 0.6,
CHCl3). IR (cm21): 3339, 2952, 2860, 1768, 1705, 1538,
1
1484, 1467, 1389, 1361, 1193, 1124, 871, 717. H NMR
(400 MHz, CDCl3): d ¼ 8.28 (br, 2H), 7.74 (br, 4H), 7.58
(br, 4H), 7.08 (s, 4H), 6.95 (s, 4H), 4.98 (br, 2H), 4.25–
4.04 (m, 8H), 3.82 (br, 4H), 3.83–3.34 (m, 4H), 2.53 (br,
2H), 2.15–1.96 (m, 6H), 1.75–1.54 (m, 8H), 1.26 (s, 18H),
3.3.1 Catalyst 4a and 4b
1.22–1.11 (m, 4H), 1.06 (s, 18H), 0.98–0.83 (m, 4H). 13
C
Catalyst 4a. Crystalline solid, 0.203 g, 84% yield; mp
25
NMR (100 MHz, CDCl3): d ¼ 212.0, 168.8, 149.1, 147.6,
133.8, 132.8, 131.9, 127.9, 125.9, 125.6, 125.4, 123.1,
53.3, 34.1, 33.8, 32.4, 31.6, 31.1, 25.2. Anal. Calcd. for
C80H98N6O4S2 (1271.80): C, 75.60; H, 7.80; N, 6.60%.
Found: C, 75.67; H, 7.72; N, 6.65%.
170–1738C, ½aꢀD þ 4.05 (c 1.0, CHCl3). Catalyst 4b.
Crystalline solid, 0.198 g, 82% yield; mp 172–1748C;
½aꢀ2D5 24.94 (c 0.9, CHCl3). IR (cm21): 3327, 2952, 2930,
2861, 1540, 1484, 1361, 1299, 1195, 1124, 1096. 1H NMR
(400 MHz, CDCl3): d ¼ 7.90 (br s, 2H), 7.07 (s, 4H), 6.86

Supramolecular Chemistry
297
(s, 4H), 4.23–4.00 (m, 12H), 3.37 (t, J ¼ 13.4 Hz, 4H),
2.78 (br s, 6H), 2.47–2.20 (m, 6H), 2.04–1.78 (m, 4H),
1.68–1.50 (m, 4H), 1.26 (s, 18H), 1.25–1.03 (m, 8H), 1.01
(s, 18H); NH-signals could not be detected. 13C NMR
(100 MHz, CDCl3): d ¼ 179.1, 168.8, 149.5, 149.2, 147.5,
142.8, 132.5, 127.6, 125.9, 125.8, 125.5, 125.4, 55.8, 34.0,
33.9, 32.1, 31.6, 30.9, 29.4, 24.8. Anal. Calcd. for
C64H94N6O4S2 (1075.60): C, 71.47; H, 8.81; N, 7.81%.
Found: C, 71.54; H, 8.73; N, 7.75%.
7.31–7.17 (m, 3H), 7.16–7.09 (m, 2H), 4.81–4.75 (dd,
J ¼ 11.3, 13.1 Hz), 4.64–4.60 (dd, J ¼ 4.2, 13.1 Hz, 1H),
3.71 (dd, J ¼ 4.2, 11.3 Hz, 1H), 1.06 (s, 3H), 0.93 (s, 3H).
IR (cm21): 3033, 2969, 2930, 2815, 1723, 1602, 1549,
1456, 1378, 1204, 1090, 912, 881, 803, 750, 703. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
0.7 mL/min, l ¼ 254 nm): tr (major) ¼ 18.26 min, tr
(minor) ¼ 26.84 min.
3.4 Synthesis of p-tert-butylphenol analogue 4c
3.5.2 (R)-3-(4-Fluorophenyl)-2,2-dimethyl-4-
nitrobutanal (5b)
25
The protected thiourea–amine 3c (0.4 g, 0.834 mmol) and
hydrazine hydrate (0.3 mL, 85% in H2O) were dissolved in
EtOH (10 mL) and refluxed for 1 h. The reaction mixture
was then cooled to rt and diethyl ether was added to
precipitate phthaloyl hydrazide. The white solid was
filtered and the filtrate was evaporated under vacuum to
afford 4c. This was used in the asymmetric Michael
addition reaction without further purification.
Light yellow oil, 40.7 mg, 85% yield. ½aꢀD þ 2.6 (c 0.5,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.50 (s, 1H),
7.20–7.14 (m, 2H), 7.06–6.98 (m, 2H), 4.84–4.78 (dd,
J ¼ 11.4, 13.0 Hz, 1H), 4.70–4.66 (dd, J ¼ 4.2, 13.1 Hz,
1H), 3.79–3.75 (dd, J ¼ 4.2, 11.4 Hz, 1H), 1.12 (s, 3H),
1.00 (s, 3H). IR (cm21): 2970, 2927, 2874, 2721, 1722,
1606, 1553, 1511, 1437, 1379, 1226, 1164, 1016, 909, 841,
750, 687. HPLC (CHIRALPAK OD-H, hexane–i-
PrOH ¼ 80:20, flow rate 0.7 mL/min, l ¼ 254 nm), tr
(major) ¼ 15.53 min, tr (minor) ¼ 27.18 min.
3.4.1 Catalyst 4c
25
Crystalline solid, 0.26 g, 89% yield; mp 95–988C; ½aꢀD
21.05 (c 2.0, CHCl3). IR (cm21): 3286, 2928, 2855, 1576,
1532, 1513, 1459, 1340, 1322, 1293, 1246, 1225, 1184,
1
1048, 910, 828, 706, 678. H NMR (400 MHz, CDCl3):
3.5.3 (R)-3-(4-Chlorophenyl)-2,2-dimethyl-4-
nitrobutanal (5c)
25
d ¼ 7.24–7.20 (m, 2H), 6.77–6.73 (m, 2H), 4.12–4.01
(m, 2H), 3.98–3.81 (m, 2H), 2.51–2.45 (m, 1H), 2.22 (br
s, 4H), 1.91 (br, 1H), 1.76 (br, 1H), 1.70–1.56 (m, 2H),
1.22 (s, 9H), 1.15–1.05 (m, 5H). 13C NMR (100 MHz,
CDCl3): d ¼ 182.4, 155.2, 142.9, 125.3, 113.0, 65.8, 57.2,
55.0, 43.7, 40.5, 33.6, 33.1, 31.2, 30.5, 23.8, 23.7, 17.4.
Anal. Calcd. for C19H31N3OS (349.53): C, 65.29; H, 8.94;
N, 12.02%. Found: C, 65.41; H, 8.87; N, 11.93%.
Colourless oil, 45.5 mg, 89% yield. ½aꢀD þ 2.8 (c 0.6,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.49 (s, 1H),
7.33–7.28 (m, 2H), 7.17–7.10 (m, 2H), 4.84–4.78 (dd,
J ¼ 11.4, 13.1 Hz, 1H), 4.70–4.66 (dd, J ¼ 4.2, 13.1 Hz,
1H), 3.78–3.74 (dd, J ¼ 4.2, 11.4 Hz, 1H), 1.11 (s, 3H),
1.00 (s, 3H). IR (cm21): 2973, 2933, 2874, 2818, 2720,
1721, 1551, 1494, 1436, 1377, 1206, 1093, 1015, 882, 835,
785, 722, 667. HPLC (CHIRALPAK OD-H, hexane–i-
PrOH ¼ 80:20, flow rate 0.7 mL/min, l ¼ 254 nm), tr
(major) ¼ 16.86 min, tr (minor) ¼ 26.71 min.
3.5 General procedure for the Michael reaction
The aldehyde (0.6mmol) was added to a mixture of catalyst
4a–4c (0.03 mmol, 15mol %) and corresponding nitroalk-
ene (0.2mmol) in 1.0 mL solvent. The reaction mixture was
stirred at rt for needful time as indicated in Tables 1–3. After
nitroalkene was consumed by TLC analysis, the reaction
mixture was subjected to flash column chromatography on
silicageltoaffordthecorrespondingproducts5a/5a0 –5u/5u0
in pure form. Compounds 5a–5u are known and the spectra
and other data were consistent with the reported values (6e,
6f, 6 g, 6 h, 9, 10b, 10h and 15). Racemic samples of the
Michael adducts were prepared using racemic catalyst 4.
3.5.4 (R)-3-(2-Bromophenyl)-2,2-dimethyl-4-
nitrobutanal (5d)
25
Orange oil, 49.2 mg, 82% yield. ½aꢀD þ 2.4 (c 0.4, CHCl3).
1H NMR (400 MHz, CDCl3): d ¼ 9.49 (s, 1H), 7.56–7.54
(dd, J ¼ 1.2, 8.1 Hz, 1H), 7.28–7.19 (m, 2H), 7.11–7.06
(m, 1H), 4.79–4.73 (dd, J ¼ 11.3, 13.2 Hz, 1H), 4.67–4.63
(dd, J ¼ 4.1, 13.3 Hz, 1H), 4.57–4.54 (dd, J ¼ 4.0,
11.3 Hz, 1H), 1.11 (s, 3H), 1.03 (s, 3H). IR (cm21): 2973,
2818, 2720, 1723, 1553, 1471, 1435, 1377, 1023, 881, 754,
663. HPLC (CHIRALPAK OD-H, hexane–i-
PrOH ¼ 80:20, flow rate 0.8 mL/min, l ¼ 254 nm), tr
(major) ¼ 14.19 min, tr (minor) ¼ 37.30 min.
3.5.1 (R)-2,2-Dimethyl-4-nitro-3-phenylbutanal (5a)
25
Light yellow oil, 39.4 mg, 89% yield. ½aꢀD þ 7.2 (c 0.5,
1
CHCl3). H NMR (400 MHz, CHCl3): d ¼ 9.54 (s, 1H),

298
M. Durmaz and A. Sirit
3.5.5 (R)-3-(3-Bromophenyl)-2,2-dimethyl-4-
nitrobutanal (5e)
25
0.7 mL/min, l ¼ 254 nm), tr (major) ¼ 11.57 min, tr
(minor) ¼ 17.72 min.
Yellow oil, 47.4 mg, 79% yield. ½aꢀD þ 2.7 (c 0.6,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.43 (s, 1H),
7.39–7.36 (m, 1H), 7.30–7.29 (m, 1H), 7.17–7.07 (m,
2H), 4.79–4.72 (dd, J ¼ 11.3, 13.3 Hz, 1H), 4.64–4.60
(dd, J ¼ 4.1, 13.3 Hz, 1H), 3.70–3.66 (dd, J ¼ 4.1,
11.3 Hz, 1H), 1.07 (s, 3H), 0.95 (s, 3H). IR (cm21):
2970, 2818, 2719, 1725, 1549, 1476, 1432, 1377, 1262,
1201, 1077, 998, 882, 804, 778, 701, 670. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow
rate 0.8 mL/min, l ¼ 254 nm), tr (major) ¼ 17.29 min, tr
(minor) ¼ 27.14 min.
3.5.9 (R)-2,2-Dimethyl-4-nitro-3-p-tolylbutanal (5i)
25
Light yellow oil, 44.7 mg, 95% yield. ½aꢀD þ 4.1 (c 0.4,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.46 (s, 1H),
7.06 (d, J ¼ 8.3 Hz, 2H), 7.00 (d, J ¼ 8.2 Hz, 2H), 4.79–
4.73 (dd, J ¼ 11.3, 12.9 Hz, 1H), 4.62–4.58 (dd, J ¼ 4.2,
13.0 Hz, 1H), 3.69–3.65 (dd, J ¼ 4.2, 11.3 Hz, 1H), 2.25
(s, 3H), 1.06 (s, 3H), 0.93 (s, 3H). IR (cm21): 2974, 2923,
2819, 2720, 1722, 1551, 1467, 1436, 1378, 1120, 882, 825,
721, 688. HPLC (CHIRALPAK OD-H, hexane–i-
PrOH ¼ 80:20, flow rate 1.0 mL/min, l ¼ 254 nm), tr
(major) ¼ 9.51 min, tr (minor) ¼ 13.12 min.
3.5.6 (R)-3-(4-Bromophenyl)-2,2-dimethyl-4-
nitrobutanal (5f)
Crystalline solid, 54.6 mg, 91% yield; mp 85–868C,
3.5.10 (R)-3-(2-Methoxyphenyl)-2,2-dimethyl-4-
nitrobutanal (5j)
1
25
½aꢀD þ 2.7 (c 0.7, CHCl3). H NMR (400 MHz, CDCl3):
d ¼ 9.43 (s, 1H), 7.41–7.39 (d, J ¼ 8.5 Hz, 2H), 7.03–
7.01 (d, J ¼ 8.4 Hz, 2H), 4.78–4.72 (dd, J ¼ 11.4,
13.2 Hz, 1H), 4.64–4.60 (dd, J ¼ 4.2, 13.1 Hz, 1H),
3.71–3.67 (dd, J ¼ 4.2, 11.4 Hz, 1H), 1.05 (s, 3H), 0.94 (s,
3H). IR (cm21): 2970, 2927, 2815, 2718, 1721, 1551,
1491, 1435, 1412, 1377, 1208, 1112, 1076, 1010, 882, 831,
781, 754, 719. HPLC (CHIRALPAK OD-H, hexane–i-
PrOH ¼ 80:20, flow rate 0.7 mL/min, l ¼ 254 nm), tr
(major) ¼ 19.48 min, tr (minor) ¼ 28.45 min.
Yellow oil, 40.7 mg, 81% yield. ½aꢀ2D5 212.5(c 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): d ¼ 9.44 (s, 1H), 7.22–7.17
(m, 1H), 7.07–7.04 (dd, J ¼ 1.7, 7.6 Hz, 1H), 6.88–6.80
(m, 2H), 4.86–4.80 (dd, J ¼ 10.8, 13.0 Hz, 1H), 4.68–4.64
(dd, J ¼ 4.6, 13.0 Hz, 1H), 4.16–4.13 (br, 1H), 3.75 (s, 3H),
1.03 (s, 3H), 0.99 (s, 3H). IR (cm21): 2971, 2841, 2725,
1723, 1601, 1551, 1439, 1378, 1245, 1056, 1026, 882, 799,
755, 712. HPLC (CHIRALPAK OD-H, hexane–i-
PrOH ¼ 80:20, flow rate 0.7 mL/min, l ¼ 254 nm), tr
(major) ¼ 11.85 min, tr (minor) ¼ 18.48 min.
3.5.7 (R)-2,2-Dimethyl-4-nitro-3-(2-nitrophenyl)
butanal (5 g)
25
3.5.11 (R)-3-(3-Methoxyphenyl)-2,2-dimethyl-4-
nitrobutanal (5k)
25
Yellow oil, 43.7 mg, 82% yield. ½aꢀD þ 91.3 (c 0.6,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.49 (s, 1H),
Colourless oil, 41.2 mg, 82% yield. ½aꢀD 22.8 (c 0.4,
7.79–7.77 (m, 1H), 7.57–7.52 (m, 1H), 7.45–7.37 (m,
2H), 4.89–4.82 (m, 1H), 4.72–4.60 (m, 2H), 1.13 (s, 3H),
1.08 (s, 3H). IR (cm21): 2973, 2818, 1722, 1553, 1525,
1470, 1446, 1377, 1352, 1302, 1203, 880, 855, 787, 670.
HPLC (CHIRALPAK AD-H, hexane–i-PrOH ¼ 85:15,
flow rate 0.7 mL/min, l ¼ 254 nm), tr (major) ¼ 20.66
min, tr (minor) ¼ 23.39 min.
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.45 (s, 1H),
7.17 (d, J ¼ 8.0 Hz, 1H), 6.77–6.65 (m, 3H), 4.79–4.73
(dd, J ¼ 11.2, 13.1 Hz, 1H), 4.62–4.58 (dd, J ¼ 4.2,
13.1 Hz, 1H), 3.72 (s, 3H), 3.69–3.66 (dd, J ¼ 4.2,
11.2 Hz, 1H), 1.07 (s, 3H), 0.95 (s, 3H). IR (cm21): 2970,
2839, 2718, 1723, 1553, 1492, 1467, 1437, 1379,
1261, 1162, 1043, 880, 800, 781, 707. HPLC (CHIR-
ALPAK OD-H, hexane–i-PrOH ¼ 91:9, flow rate
0.8 mL/min, l ¼ 254 nm), tr (major) ¼ 43.30 min, tr
(minor) ¼ 45.10 min.
3.5.8 (R)-3-(Furan-2-yl)-2,2-dimethyl-4-nitrobutanal
(5 h)
25
Orange oil, 33.8 mg, 80% yield. ½aꢀD 213.3 (c 0.5,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.45 (s, 1H),
3.5.12 (R)-3-(4-Methoxyphenyl)-2,2-dimethyl-4-
nitrobutanal (5 l)
25
7.30 (d, J ¼ 1.9 Hz, 1H), 6.25–6.24 (dd, J ¼ 1.8, 3.3 Hz,
1H), 6.15 (d, J ¼ 3.3 Hz, 1H), 4.71–4.65 (m, 1H), 4.54–
4.50 (dd, J ¼ 3.9, 12.9 Hz, 1H), 3.87–3.83 (dd, J ¼ 3.9,
11.0 Hz, 1H), 1.11 (s, 3H), 0.98 (s, 3H). IR (cm21):
2974, 2818, 2719, 1725, 1553, 1468, 1433, 1376, 1148,
1078, 1016, 914, 885, 815, 738, 700. HPLC (CHIR-
ALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
Light yellow oil, 42.2 mg, 84% yield. ½aꢀD 2 2.3(c 0.6,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.45 (s, 1H),
7.05–7.03 (d, J ¼ 8.7 Hz, 2H), 6.79–6.77 (d, J ¼ 8.8 Hz,
2H), 4.76–4.70 (dd, J ¼ 11.4, 12.9 Hz, 1H), 4.61–4.57
(dd, J ¼ 4.3, 12.9 Hz, 1H), 3.72 (s, 3H), 3.68–3.64 (dd,

Supramolecular Chemistry
299
J ¼ 4.3, 11.4 Hz, 1H), 1.05 (s, 3H), 0.93 (s, 3H). IR
3.5.16 (R)-1-[1-(3-Methoxyphenyl)-2-nitroethyl]
cyclopentanecarbaldehyde (5p)
25
(cm21): 747, 836, 882, 1032, 1182, 1250, 1379, 1465,
1514, 1551, 1611, 1722, 2718, 2839, 2969. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow
rate 0.7 mL/min, l ¼ 254 nm), tr (major) ¼ 20.27 min, tr
(minor) ¼ 29.12 min.
Colourless oil, 39.9 mg, 72% yield. ½aꢀD 2 2.2 (c 0.4,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.48 (s, 1H),
7.25–7.19 (m, 1H), 6.82–6.70 (m, 3H), 4.96–4.90 (dd,
J ¼ 11.2, 13.2 Hz, 1H), 4.69–4.65 (dd, J ¼ 3.8, 13.2 Hz,
1H), 3.77 (s, 3H), 3.66–3.63 (dd, J ¼ 3.8, 11.2 Hz, 1H),
2.09–2.00 (m, 1H), 1.92–1.84 (m, 1H), 1.71–1.50
(m, 6H). IR (cm21): 2958, 2871, 2836, 2727, 1718,
1601, 1585, 1552, 1492, 1455, 1438, 1378, 1321,
1292, 1261, 1160, 1045, 876, 787, 704. HPLC (CHIR-
ALPAK OD-H, hexane–i-PrOH ¼ 95:5, flow rate
0.6 mL/min, l ¼ 254 nm), tr (major) ¼ 53.32 min, tr
(minor) ¼ 56.06 min.
3.5.13 (R)-1-(2-Nitro-1-phenylethyl)cyclopentanecarbal
dehyde (5 m)
25
Colourless oil, 35.1 mg, 71% yield. ½aꢀD 2 9.4 (c 0.4,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.42 (s, 1H,
CHO), 7.27–7.21 (m, 3H), 7.14–7.11 (m, 2H), 4.93–4.86
(dd, J ¼ 11.3, 13.1 Hz, 1H), 4.65–4.61 (dd, J ¼ 3.8,
13.2 Hz, 1H), 3.65–3.61 (dd, J ¼ 3.8, 11.3 Hz, 1H), 2.04–
1.93 (m, 1H), 1.85–1.79 (m, 1H), 1.60–1.45 (m, 6H). IR
(cm21): 2954, 2870, 2720, 1719, 1551, 1496, 1455, 1378,
1203, 1127, 911, 879, 790, 751, 702. HPLC (CHIR-
ALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 11.54 min, tr
(minor) ¼ 15.90 min.
3.5.17 (R)-1-(1-(4-Methoxyphenyl)-2-nitroethyl)
cyclopentanecarbaldehyde (5q)
25
Yellow oil, 42.2 mg, 76% yield. ½aꢀD 2 3.6 (c 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): d ¼ 9.47 (s, 1H), 7.10 (d,
J ¼ 8.8 Hz, 2H), 6.82 (d, J ¼ 8.8 Hz, 2H), 4.93–4.87 (dd,
J ¼ 11.4, 13.0 Hz, 1H), 4.67–4.63 (dd, J ¼ 3.9, 13.0 Hz,
1H), 3.77 (s, 3H), 3.65–3.62 (dd, J ¼ 3.9, 11.4 Hz, 1H),
2.07–1.96 (m, 1H), 1.90–1.85 (m, 1H), 1.66–1.51 (m, 6H).
IR (cm21): 2957, 2871, 2721, 1719, 1611, 1552, 1514,
1442, 1379, 1297, 1251, 1182, 1119, 1033, 835, 814, 726.
HPLC (CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20,
flow rate 1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 12.55
min, tr (minor) ¼ 16.96 min.
3.5.14 (R)-1-(2-Nitro-1-p-tolylethyl)
cyclopentanecarbaldehyde (5n)
25
Colourless oil, 39.2 mg, 75% yield. ½aꢀD 2 4.1 (c 0.5,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.48 (s, 1H),
7.13–7.04 (m, 4H), 4.94–4.88 (dd, J ¼ 11.4, 13.0 Hz,
1H), 4.68–4.64 (dd, J ¼ 3.9, 13.0 Hz, 1H), 3.67–3.63
(dd, J ¼ 3.9, 11.4 Hz, 1H), 2.30 (s, 3H), 2.08–1.99
(m, 1H), 1.92–1.83 (m, 1H), 1.66–1.48 (m, 6H).
IR (cm21): 2954, 2870, 2724, 1720, 1553, 1452, 1436,
1378, 1311, 1190, 1121, 1040, 823, 721. HPLC (CHIR-
ALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 9.21 min, tr
(minor) ¼ 12.37 min.
3.5.18 (R)-1-(1-(2-Bromophenyl)-2-nitroethyl)
cyclopentanecarbaldehyde (5r)
25
Light green oil, 51.5 mg, 79% yield. ½aꢀD 2 1.6 (c 0.3,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.45 (s, 1H),
7.54–7.52 (m, 1H), 7.26–7.23 (m, 2H), 7.10–7.04 (m,
1H), 4.91–4.85 (dd, J ¼ 11.2, 13.3 Hz, 1H), 4.66–4.62
(dd, J ¼ 3.9, 13.3 Hz, 1H), 4.50–4.46 (dd, J ¼ 3.8,
11.2 Hz, 1H), 2.08–1.96 (m, 1H), 1.85–1.78 (m, 1H),
1.70–1.45 (m, 6H). IR (cm21): 2956, 2870, 2724, 1721,
1553, 1472, 1434, 1377, 1202, 1023, 754, 723, 662. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 11.09 min, tr
(minor) ¼ 32.61 min.
3.5.15 (R)-1-[1-(2-Methoxyphenyl)-2-nitroethyl]
cyclopentanecarbaldehyde (5o)
25
Light yellow oil, 38.8 mg, 70% yield. ½aꢀD 2 2.5 (c 0.3,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.46 (s, 1H),
7.27–7.23 (m, 1H), 7.13–7.11 (dd, J ¼ 1.7, 7.6 Hz, 1H),
6.92–6.85 (m, 2H), 5.02–4.96 (dd, J ¼ 11.1, 12.7 Hz,
1H), 4.73–4.69 (dd, J ¼ 4.2, 12.9 Hz, 1H), 4.05 (br s, 1H),
3.80 (s, 3H), 2.13–2.06 (m, 1H), 1.85–1.80 (m, 1H),
1.65–1.46 (m, 6H). IR (cm21): 2952, 2870, 2843,
2724, 1719, 1601, 1587, 1552, 1494, 1464, 1439, 1379,
1339, 1292, 1247, 1124, 1055, 1026, 756. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow
rate 1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 7.85 min, tr
(minor) ¼ 11.86 min.
3.5.19 (R)-1-(1-(3-Bromophenyl)-2-nitroethyl)
cyclopentanecarbaldehyde (5s)
25
Colourless oil, 48.9 mg, 75% yield. ½aꢀD 2 2.3 (c 0.3,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.45 (s, 1H),
7.43–7.40 (m, 1H), 7.66 (t, J ¼ 1.8 Hz, 1H), 7.22–7.13
(m, 2H), 4.99–4.93 (dd, J ¼ 11.3, 13.4 Hz, 1H), 4.70–
4.65 (dd, J ¼ 3.6, 13.4 Hz, 1H), 3.64–3.61 (dd, J ¼ 3.6,

300
M. Durmaz and A. Sirit
11.2 Hz, 1H), 2.10–2.00 (m, 1H), 1.90–1.85 (m, 1H),
1.72–1.55 (m, 6H). IR (cm21): 2956, 2870, 2730, 1719,
1594, 1551, 1476, 1432, 1377, 1262, 1200, 1077, 997, 907,
790, 732, 698, 670. HPLC (CHIRALPAK OD-H, hexane–
i-PrOH ¼ 80:20, flow rate 1.0 mL/min, l ¼ 254 nm), tr
(major) ¼ 12.40 min, tr (minor) ¼ 17.32 min.
Acknowledgements
We gratefully acknowledge financial support from the Scientific
and Technological Research Council of Turkey (TUBITAK) and
Necmettin Erbakan University.
References
(1) For reviews on organocatalysis, see: (a) Berkessel, A.;
Groger, H. Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2005; (b)
Dalko, P.I., Ed.; Enantioselective Organocatalysis; Wiley-
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3.5.20 (R)-1-(1-(4-Bromophenyl)-2-nitroethyl)
cyclopentanecarbaldehyde (5t)
25
Colourless oil, 53.5 mg, 82% yield. ½aꢀD 2 4.2 (c 0.4,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.44 (s, 1H),
7.44 (d, J ¼ 8.4 Hz, 2H), 7.08 (d, J ¼ 8.6 Hz, 2H), 4.98–
4.92 (dd, J ¼ 11.5, 13.3 Hz, 1H), 4.69–4.65 (dd, J ¼ 3.7,
13.3 Hz, 1H), 3.65–3.61 (dd, J ¼ 3.7, 11.4 Hz, 1H), 2.05–
1.99 (m, 1H), 1.89–1.82 (m, 1H), 1.70–1.54 (m, 6H). IR
(cm21): 2955, 2869, 2724, 1718, 1552, 1490, 1437, 1411,
1377, 1202, 1114, 1076, 1010, 830, 781, 718. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 13.54 min, tr
(minor) ¼ 17.06 min.
3.5.21 (R)-1-(1-(4-Chlorophenyl)-2-nitroethyl)
cyclopentanecarbaldehyde (5u)
25
Colourless oil, 47.3 mg, 84% yield. ½aꢀD 2 5.1 (c 0.3,
1
CHCl3). H NMR (400 MHz, CDCl3): d ¼ 9.44 (s, 1H),
7.31–7.26 (m, 2H), 7.17–7.12 (m, 2H), 4.98–4.92 (dd,
J ¼ 11.4, 13.3 Hz, 1H), 4.69–4.65 (dd, J ¼ 3.7, 13.3 Hz,
1H), 3.67–3.63 (dd, J ¼ 3.7, 11.4 Hz, 1H), 2.08–1.99 (m,
1H), 1.91–1.83 (m, 1H), 1.71–1.53 (m, 6H). IR (cm21):
2958, 2871, 2729, 1718, 1551, 1494, 1436, 1377, 1303,
1202, 1093, 1014, 834, 787, 758, 720, 666. HPLC
(CHIRALPAK OD-H, hexane–i-PrOH ¼ 80:20, flow rate
1.0 mL/min, l ¼ 254 nm), tr (major) ¼ 11.97 min, tr
(minor) ¼ 15.40 min.
4. Conclusion
In conclusion, for the first time, a novel class of
calix[4]arene-based chiral bifunctional primary amine–
thiourea catalysts 4a and 4b have been developed as
efficient organocatalysts for the asymmetric Michael
addition of isobutyraldehyde and cyclopentanecarboxal-
dehyde to nitroalkenes. The reactions proceeded smoothly
in CH2Cl2 at rt to give high yields (up to 95%) and (ee up
to 99%) with broad substrate scope. Chiral catalyst 4a
preferentially furnishes the (R)-enantiomer, whereas 4b
selectively produces the (S)-enantiomer. Further studies
regarding the mechanism details and application of the
catalytic system in other asymmetric CZC bond-forming
reactions are currently under investigation.
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