Chiral Cu(II) complexes as recyclable catalysts for asymmetric nitroaldol (Henry) reaction in ionic liquids as greener reaction media

Article abstract of DOI:10.1007/s10562-010-0443-8

Chiral Cu (II) complexes generated in situ from C₂-symmetric chiral secondary bis-amines 1′-4′ based on 1,2-diaminocyclohexane structure having H, t-Bu and Cl substituents at 3, 3′, 4, 4′ and 5, 5′ with copper acetate. They were used as catalys

Full text of DOI:10.1007/s10562-010-0443-8

Catal Lett (2010) 140:189–196
DOI 10.1007/s10562-010-0443-8
Chiral Cu(II) Complexes as Recyclable Catalysts for Asymmetric
Nitroaldol (Henry) Reaction in Ionic Liquids as Greener Reaction
Media
•
Noor-ul Hasan Khan Eko Adi Prasetyanto
•
•
Young-Ki Kim Mohd Bismillah Ansari
•
Sang-Eon Park
Received: 13 July 2010 / Accepted: 20 August 2010 / Published online: 8 September 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Chiral Cu (II) complexes generated in situ from
C2-symmetric chiral secondary bis-amines 10–40 based on
1,2-diaminocyclohexane structure having H, t-Bu and Cl
substituents at 3, 30, 4, 40 and 5, 50 with copper acetate.
They were used as catalysts for an environmentally benign
protocol for highly enantioselective nitroaldol reaction of
various aldehydes with nitromethane in the presence of
different ionic liquids as a greener reaction medium at
0 °C. Excellent yields (up to 90% with respect to aldehyde)
of b-nitroalcohols with high enantioselectivity (ee, up to
94%) was achieved when [emim]BF4 was used as ionic
liquid. The present ionic liquid mediated nitroaldol proto-
col is recyclable (up to five cycles) with no significant loss
in its performance.
in asymmetric synthesis of charily pure nitroalcohols, which
are valuable precursors for a wide range of synthetic targets
including (R)-denopamine and (R)-arbutamine. The nitro
group in the product can further be conveniently converted
into several other functionalities to give synthetically and
biologically important bi-functional compounds [1]. In
particular, reduction of b-hydroxynitroalkanes gives ready
access to b-amino alcohols, which are now extensively used
as chiral ligands in asymmetric catalysis and as important
building blocks for the synthesis of natural products phar-
maceuticals [2]. In spite of many applications, the catalytic
enantioselective version of nitroaldol reaction is relatively
less explored as compared to its aldol counterpart due to the
non-availability of enantioselective catalysts. Shibasaki has
reported the first asymmetric version of nitroaldol reaction
in 1992 [3–11]. Since then various metals [3–7, 12–17]
and non-metal based catalysts [18, 19] have been investi-
gated for the asymmetric nitroaldol reaction with chiral
ligands such as BINOL [5, 10, 20], amino alcohol [21, 22],
bis(oxazoline) [23–31], bis(thiazoline) [32], bis(imidazo-
line) [33–35], sulfonyl diamine [36], salen [37–40], Schiff
bases [41–50], thiols [51], thiophene [52], bipiperidine
[53–57], aminopyridine [58], oxabispidines [59]. The
Cu-catalyzed nitroaldol reaction is however most explored
due to its inexpensive and less toxic nature, besides the fact
it has demonstrated high catalytic activity under homoge-
neous reaction conditions [29, 30, 34, 48, 53, 60–65].
Mechanistically, nitroaldol reaction requires both acidic and
basic sites for the activation of substrate. For this reason a
variety of bases viz., potassium hydroxide [66, 67], cetyl-
trimethyl ammonium hydroxide [68], sodium carbonate
[61], triethyl amine [61], 2,6-lutidine [36], pyridine [36] and
aromatic imines [29] have found application as additives to
improve the efficiency of typical acidic metal complexes
based catalysts in nitroaldol reactions. Although good to
Keywords Asymmetric nitroaldol reaction ꢀ Cu(II)
complex ꢀ Chiral catalysis ꢀ Ionic liquid ꢀ Recyclable
1 Introduction
The metal complex catalyzed enantioselective nitroaldol
(Henry) reaction is an attractive and quite powerful method
N. H. Khan ꢀ E. A. Prasetyanto ꢀ Y.-K. Kim ꢀ
M. B. Ansari ꢀ S.-E. Park (&)
Laboratory of Nano-Green Catalysis and Nano Center for Fine
Chemical Fusion Technology, Department of Chemistry,
Inha University, Incheon 402-751, Korea
e-mail: separk@inha.ac.kr
N. H. Khan
Discipline of Inorganic Materials and Catalysis, Central Salt
and Marine Chemicals Research Institute (CSMCRI),
Council of Scientific & Industrial Research (CSIR),
G B Marg, Bhavnagar 364-002, Gujarat, India
123

190
N. H. Khan et al.
excellent optical purities were obtained for b-nitroalcohols,
most of these methods suffer from limitations, such as rel-
atively high catalyst loading, low reaction temperatures,
multistep synthetic procedures for ligand preparation and
non-recyclability of the catalysts. As the chiral catalyst are
very expensive, their recyclability is an important aspect for
economical and scaling-up point of view. There are only few
reports [68] available on asymmetric nitroaldol reaction
where catalyst can be recycled but demand major modifi-
cation in the structure of the catalyst.
HN
HN
NH
NH
Cl
Cl
Cl
Cl
1'
2'
To overcome this problem, ionic liquids are currently
viewed as future reaction media in chemical industry as an
eco-friendly alternative to the conventionally used hazard-
ous organic solvents [69, 70]. It has also been observed that
switching over to an ionic liquid from traditional organic
solvents often results in a significant improvement in reac-
tivity and selectivity of a catalytic system [71–74]. More-
over, ionic liquids also facilitate catalyst recyclability.
Among the room temperature ionic liquids (RTILs),
1,3-dialkylimidazolium salts have emerged as leading con-
tenders suitable for multi-phase catalysis for various organic
transformations. Herein, we are reporting for the first time
the use of ionic liquid as greener media for asymmetric
nitroaldol reaction of various aldehyde with nitromethane
using in situ generated chiral Cu (II) complexes by the
reaction of copper acetate with C2-symmetric chiral sec-
ondary bis-amines based on chiral 1,2-diaminocyclohexane
structure having H, t-Bu and Cl substituent at 3, 30, 4, 40 and
5, 50 positions of phenyl groups. Excellent yield with high
enantiomeric excess (ee, 94%) of chiral b-nitrolcohol was
achieved when [emim]BF4 was used as ionic liquid with
added advantage of catalyst recyclability.
HN
HN
NH
NH
OH HO
OH HO
OEt
EtO
3'
Fig. 1 Structure of the chiral ligands (10–40)
4'
taken in ethanol (20 mL), to which (1S, 2S)-(?)-1,2-
diaminocyclohexane (0.5 mmol) was added at 0 °C. The
reaction mixture was then stirred at this temperature for 1 h
then refluxed for 10–12 h. After completion of the reaction
(checked on TLC), it was cooled to room temperature and
4 mmol of sodium borohydride was slowly added with
stirring. The resulting solution thus obtained was refluxed
for 10 h. Subsequently, the solvent was removed on rota-
evaporator and the resulting mass was washed with distilled
water and extracted with dichloromethane. The organic
layer was dried over anhydrous sodium sulphate and evap-
orated to get the desired product as viscous solid. The
characterization of the ligands was accomplished by dif-
ferent physicochemical methods, which matched well with
the earlier reports [46, 48, 75].
2 Experimental
2.2.1 (1S,2S)-N,N-Bis(3-Chlorobenzyl)Cyclohexane-1,
2-Diamine (10)
2.1 Materials and Methods
1
Pale yellow solid, m.p. = 60–64 °C. HNMR (200 MHz,
CDCl3): d = 0.89–1.76 (m, 8H), 1.88 (brs, 2H), 2.14–2.26
(m, 2H), 3.57 (d, J = 13 Hz, 4H), 7.14–7.40 (m, 8H).
Solvents were dried according to the standard procedures
and distilled prior to their use. Most reagents and ionic
liquids were purchased from Aldrich or Across Chemicals
and were used as received. 1H NMR spectra were recorded
at 200 MHz (Varian) in CDCl3 as solvent and tetrameth-
ylsilane was used as an internal standard. The enantiomeric
excess was determined by HPLC (Agilent 1200 Series) on
Chiralcel OD-H column.
25
½aꢁD ¼ þ75 (c = 1, CH2Cl2). IR: 3300, 3045, 2919, 2840,
1590, 1560, 1450, 1220, 1110, 860, 770 cm-1
.
2.2.2 (1S,2S)-N,N-Bis(4-Chlorobenzyl)Cyclohexane-1,
2-Diamine (20)
Colourless oil. 1HNMR (200 MHz, CDCl3): d = 0.90–1.70
(m, 8H), 1.80 (brs, 2H), 2.15–2.25 (m, 2H), 3.57(d, J =
25
2.2 Synthesis of Chiral Ligands 10–40
The chiral ligands 10–40 (Fig. 1) were synthesized by the
modified reported procedure [46, 48, 75]. In a 100 mL round
bottom flask aldehyde/substituted aldehydes (1 mmol) was
13 Hz, 4H) 7.10–7.35 (m, 8H). ½aꢁD ¼ þ60 (c = 1,
CH2Cl2). IR: 3280, 3010, 2900, 2815, 1575, 1460, 1410,
1200, 1135, 810, 765 cm-1
.
123

Chiral Cu(II) Complexes as Recyclable Catalysts
191
2.2.3 6,60-(1S,2S)-Cyclohexane-1,2-Diylbis(Azanediyl)
various aldehydes are as follows and all the values well
matched with the reported literature.
Bis(Methylene)Bis(2-Ethoxyphenol) (30)
1
Light yellow oil. HNMR (200 MHz, CDCl3): d = 1.20
(m, 4H), 1.41 (t, J = 7, 6H), 1.63 (m, 4H), 2.07 (m, 2H),
2.3.1 (R)-2-Nitro-1-Phenylethanol
Colorless oil. 1H NMR (200 MHz, CDCl3): d = 2.89 (br s,
1H), 4.39–4.43 (m, 2H), 5.34 (m, 1H), 7.13–7.33 (m, 5H;
ArH) ppm; 13CNMR (50 MHz, CDCl3): d = 69.00, 79.19,
2.35 (brs, 2H), 3.80 (d, J = 13, 4H), 3.94 (q, J = 7 Hz,
25
4H), 6.67–7.56 (m, 6H), 11.2 (brs, 2H). ½aꢁD ¼ þ45
(c = 1, CH2Cl2) IR: 3200, 2910, 1560, 1530, 1480, 1410,
1260, 1220, 1135, 1077 s, 945, 900, 834 cm-1
25
.
125.10, 128.94, 129.01, 138.11 ppm. ½aꢁD ¼ ꢂ41:5 (c =
1.0, CH2Cl2). HPLC analysis (Chiracel OD-H column,
0.8 mL/min, n-hexane/i-PrOH 90:10, k = 210 nm).
Retention times: 21.03 min [major (R)-enantiomer] and
25.99 min [minor (S)-enantiomer].
2.2.4 6,60-(1S,2S)-Cyclohexane-1,2-Diylbis(Azanediyl)
Bis(Methylene)Bis(2,4-Di-Tert-Butylphenol) (40)
White solid mp = 142–145 °C. 1HNMR (200 MHz,
CDCl3): d = 1.68–1.02 (m, 44H), 2.14 (m, 2H), 2.42 (m,
2H), 3.94 (d, J = 13, 4H), 6.90–7.20 (m, 4H), 10.70 (brs,
2.3.2 (R)-2-Nitro-1-(3-Nitrophenyl)Ethanol
Colorless oil. 1H NMR (200 MHz, CDCl3): d = 2.89 (br s,
1H), 4.60–4.57 (m, 2H), 5.62–5.60 (m, 1H), 8.30–7.29 (m,
25
25
2H). ½aꢁD ¼ þ34 (c = 0.5, CH2Cl2). IR: 3270, 2990, 1570,
1540, 1455, 1430, 1240, 1210, 1145, 1090 s, 930, 890,
800 cm-1
4H) ppm. ½aꢁD ¼ ꢂ32:5 (c = 1.01, CH2Cl2), HPLC analysis
.
(Chiracel OD-H column, 0.5 mL/min, n-hexane/i-PrOH
85:15, k = 210 nm). Retention times: 41.97 min [major
(R)-enantiomer] and 49.10 min [minor (S)-enantiomer].
2.3 General Procedure for Asymmetric Nitroaldol
Reaction
2.3.3 (R)-2-Nitro-1-(3-Chlorophenyl)Ethanol
Chiral ligands (10–40) (0.06 mmol, 12 mol.%) and
Cu(OAc)2ꢀH2O (10.0 mg, 0.05 mmol, 10 mol.%) were
mixed together in 0.125 mL absolute ethanol and the
resulting blue colour solution was stirred for 30–45 min. at
room temperature. To this solution 250 mg ionic liquid was
added and the resulting mixture was transferred into a
double wall jacketed glass reactor. To this solution aldehyde
(1 mmol) was added and allowed the mixture to be stirred
further for 15–20 min. The resulting solution was brought to
0 °C and nitromethane (5.0 mmol) was slowly added in an
interval of 1 h by using a syringe. The progress of the
reaction was checked on TLC. After 30 h the product was
separated using repetitive washing of the reaction mixture
(five times) with hexane ethyl acetate 4:1 mixture. After
complete washing, the ionic liquid containing a copper
complex was dried under vacuum and stored in desiccator
for its use in subsequent catalytic runs. The blue solution
was directly used for catalytic reaction, however the solvent
from the blue solution was evaporated and the residue was
washed several times with solvent ether and dried under
vacuum. The blue complex thus obtained was used as cat-
alyst under the identical reaction conditions in order to
compare the catalytic reactions carried out with in situ
generated catalysts. The enantiomeric excess (ee) of the
product was determined by HPLC using OD-H column with
2-PrOH/hexane (90:10) as eluent. HPLC traces of products
were compared with the respective racemic samples. Ana-
lytical data of a few chiral b-hydroxy nitroalkanes from
Colourless oil. 1H NMR (200 MHz, CDCl3): d = 3.44 (brs,
1H), 4.60–4.47 (m, 2H), 5.45–5.40 (m, 1H), 7.47–7.28 (m,
4H) ppm. 13C NMR (50 Hz, CDCl3) d = 69.2, 83.0, 123.0,
25
124.1, 126.9, 129.2, 134.8, 142.0 ppm. ½aꢁD ¼ ꢂ32:0 (c =
0.85, CH2Cl2) HPLC analysis (Chiracel OD-H column,
0.8 mL/min, n-hexane/i-PrOH 90:10, k = 210 nm). Reten-
tion times: 20.26 min [major (R)-enantiomer] and 25.91 min
[minor (S)-enantiomer].
2.3.4 (R)-2-Nitro-1-(4-Chlorophenyl)Ethanol
Colourless oil. 1H NMR (200 MHz, CDCl3): d = 2.89 (brs,
1H), 4.50–4.46 (m, 2H), 5.42–5.40 (m, 1H), 7.40–7.47 (m,
4H) ppm. 13C NMR (50 MHz, CDCl3) d = 69.67, 84.00,
25
127.30, 129.24, 134.80, 136.61 ppm. ½aꢁD ¼ ꢂ28:5 (c =
1.0, CH2Cl2) HPLC analysis (Chiracel OD-H column,
0.8 mL/min, n-hexane/i-PrOH 90:10, k = 210 nm). Reten-
tion times: 20.25 min [major (R)-enantiomer] and 26.73 min
[minor (S)-enantiomer].
2.3.5 (R)-2-Nitro-1-(4-Methoxyphenyl)-Ethanol
Colourless oil. 1H NMR (200 MHz, CDCl3): d = 2.39 (brs,
1H), 3.74 (s, 3H), 4.41–4.37 (m, 2H), 5.30 (m, 1H),
6.77–7.22 (m, 4H) ppm. 13C NMR (50 MHz, CDCl3)
d = 54.99, 70.37, 81.20, 114.39, 127.20, 130.21, 159.78
25
ppm.½aꢁD ¼ ꢂ38:0 (c = 1.02, CH2Cl2). HPLC analysis
123

192
N. H. Khan et al.
(Chiracel OD-H column, 0.8 mL/min, n-hexane/i-PrOH
90:10, k = 210 nm). Retention times: 30.63 min [major
(R)-enantiomer] and 40.28 min [minor (S)-enantiomer].
0 °C for 30 h, which gave the product in 55% yield and 84%
ee (Table 1, entry 1). However, in this reaction the catalyst
was not recyclable. In order to make the system recyclable,
we conducted this reaction in the presence of readily avail-
able 1-ethyl 3-methylimidazolium bromides ([emim][Br]) as
representative ionic liquid (entry 2). After 30 h there was an
improvement in the product yield (65%), however there was
a marginal drop in ee (78%). When the same reaction was
conducted at RT (*27 °C) there was a marginal increase in
product yield (69%) but with decreased ee (68%) (entry 3).
On conducting this reaction in the absence of ethanol, there
was a further drop in ee (61%) however the product yield
remained the same (67%) (entry 4). Only a marginal increase
in the product yield was observed for extended time (up to
48 h) for this reaction with minor increase in the product
yield (70%) with no improvement in enantioselectivity (ee
60%, entry 5). We further explored the use of other solvents
viz., THF and toluene (entries 6 and 7) for nitroaldol reaction
under the similar reaction condition, however, there was a
significant drop in the ee (48 and 34% respectively) of the
product. Therefor, it was concluded that ethanol as a co-solvent
with the ionic liquid is the reaction phase of choice.
2.3.6 (R)-3-Methyl-1-Nitrobutan-2-ol
Colourless oil, 1H NMR (200 MHz, CDCl3): d =
0.97–1.00 (m, 6H), 1.77–1.81 (m, 1H), 2.57 (s, 1H), 4.10
(s, 1H), 4.37–4.48 (m, 2H) ppm; 13C NMR (50 MHz,
25
CDCl3) d 17.4, 18.4, 31.7, 73.3, 79.2 ppm. ½aꢁD ¼ ꢂ15:8
(c = 0.95, CH2Cl2) HPLC analysis (Chiralcel OD-H,
n-hexane/i-PrOH 97:3, 0.6 mL/min, 23 °C, k = 220 nm).
Retention times: 27.6 min [minor] and 30.0 min [major].
2.3.7 (R)-1-Nitro-2-Phenyl-But-3-en-2-ol
Yellow solid, 1H NMR (200 MHz, CDCl3): d 7.37–7.26 (m,
5H), 6.75 (dd, J = 15.9 Hz, J = 1.2 Hz, 1H), 6.13 (dd,
J = 15.9 Hz, J = 6.3 Hz, 1H), 4.47–4.45 (m, 1H),
4.13–4.06 (m, 2H), 3.50 (bs, 1H) ppm; 13C NMR (50 Hz,
CDCl3) d 0.1, 78.7, 125.0, 125.9, 127.8, 128.2, 132.8,
25
135.1 ppm. ½aꢁD ¼ ꢂ12:3 (c = 1.0, CH3Cl) HPLC analysis
To evaluate the effect of increasing the carbon chain
length in ionic liquids n = 3 and 5 the nitroaldol reaction
was carried out with benzaldehyde as representative sub-
strate in 30 h (optimized condition). Unfortunately, the
decrease in product yield as well as ee was observed
(Table 1, entries 8 and 9). It is reported in the literature that
the counter anion [X-] in the ionic liquids [emim][X]
greatly influences the catalytic activity and enantioselec-
tivity of the reaction [33, 34]. Therefore, we have carried out
the nitroaldol reaction under the optimized reaction condi-
tions (Table 1, entry 3) in the presence of ionic liquids
having different anions viz., OH, BF4 and PF6 (Table 1,
entries 8–12). Basic anions like OH- adversely effected the
enantioselectivity (ee 42%, entry 10), whereas flurorinated
anions like BF4 and PF6 gave better results in terms of
product yield and enantioselectivity, BF4 being the best
among the two (entries 11 and 12). It should be noted here
that nitroaldol reaction requires a delicate balance between
acidity and basicity in the catalytic system in order to acti-
vate the starting materials aldehyde and nitromethane
respectively. Therefore, high basicity (as in the case of OH-
counterion) of the ionic liquid might cause the lowering of
product yield and enantioselectivity. On the other hand,
moisture-resistant neutral counter ions like PF6 and BF4 may
not alter the acidity or basicity of the reaction media, but
could help in the polarisation of nitromethane due to highly
electronegative character of fluorine atom. This in turn
would increase activity of the reactant as evidenced by
higher product yield in the same reaction time (for compa-
rision please see entries 10–13). On conducting the nitro-
aldol reaction of benzaldehyde with nitromethane at 0 °C in
(Chiracel OD-H column, 1.0 mL/min, n-hexane/i-PrOH
99:1, k = 205 nm). Retention times: 19.26 min [minor
(S)-enantiomer] and 21.55 min [major (R)-enantiomer].
2.3.8 (R)-(-)-1-Nitroheptan-2-ol
Colorless oil; 1H NMR (400 MHz, CDCl3): d 4.46–4.28 (m,
3H), 2.68 (b, 1H), 1.57–1.47 (m, 3H), 1.39–1.31 (m, 5H),
0.90 (t, J = 6.72 Hz, 3H); 13C NMR (100 MHz, CDCl3)
25
80.85, 68.89, 33.86, 31.63, 25.01, 22.63, 14.01 ppm. ½aꢁD
¼
ꢂ10:4 (c = 1.11, CH2Cl2) HPLC analysis (Chiracel AD-H
column, 0.9 mL/min, n-hexane/i-PrOH 90:10, k = 210 nm).
Retention times: 8.9 min [minor (S)-enantiomer] and
11.6 min [major (R)-enantiomer].
3 Results and Discussion
The chiral ligands 10–40 (Fig. 1) were synthesized by the
reduction of respective diimines with NaBH4 which in turn
were synthesized by the condensation of benzaldehyde,
4-chloro benzaldehyde, 3-ethoxy salicylaldehyde and 3,5
di-tert-butyl salicylaldehyde with (1S,2S)-(?)-1,2-diamino-
cyclohexane. The characterization of the ligands was
accomplished by 1H NMR-, IR-, UV/Vis. Spectroscopy, and
optical rotation.
Chiral ligand 10 (12 mol.%) and copper acetate (10 mol.%)
were allowed to react in ethanol and the resulting complex
was directly used as catalyst for nitroaldol reaction of
benzaldehyde with nitromethane as a model substrate at
123

Chiral Cu(II) Complexes as Recyclable Catalysts
193
Table 1 Optimization of reaction conditions for asymmetric nitroaldol reaction in ionic liquids for in situ generated chiral Cu(Oac)2ꢀH2O/ 10 as
catalyst
OH
O
NO2
1'
Cu(OAc)2.H2O (10 mol%) / (12 mol%)
CH NO
H +
3
2
Ionic liquid, EtOH
Br
N
N
[bmim]Br
X
N
N
Br
N
N
[emim] with X = Br / OH / BF4 / PF6
[hmim]Br
Entry
Ionic liquid
Solvent
T (°C)
Time (h)
Yield (%)a
ee (%)b
1
–
EtOH
EtOH
EtOH
–
0
30
30
30
30
48
30
30
30
30
30
30
30
30
30
40
40
40
55
65
69
67
70
57
47
60
41
30
71
57
82
40
52
Trace
–
84
78
68
61
60
48
34
48
27
42
79
77
86
84
–
2
[emim]Br
[emim]Br
[emim]Br
[emim]Br
[emim]Br
[emim]Br
[bmim]Br
[hxmim]Br
[emim]OH
[emim]BF4
[emim]PF6
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
0
3
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
4
5
–
5
THF
6
Toluene
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
8
9
10
11
12
13
14c
15d
16e
17f
0
0
0
–
0
–
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of in situ generated complex 1 from
a
ligand 10(12 mmol and Cu(OAc)2ꢀ2H2O (10 mol.%) in 0.125 mL of solvent and 250 mg ionic liquid at 0 °C. Isolated yields by the column
b
c
chromatography. Determined by HPLC on a OD-H column. Reaction was conducted with isolated complex (10 mol.%) from ligand 10 and
d
e
Cu(OAc)2ꢀ2H2O). The reaction was conducted in the absence of chiral ligand 10. The reaction was conducted in the absence of
f
Cu(OAc)2ꢀ2H2O. The reaction was conducted in the absence of chiral ligand 10and Cu(OAc)2ꢀ2H2O
[emim]BF4 along with ethanol as co-solvent 82% yield of
chiral b-nitroalcohol with high ee (86%) under optimized
reaction condition was obtained (Table 1, entry 13).
Further, the same reaction in the absence of copper acetate
failed to perform nitroaldol reaction (entry 16). Further-
more, when the nitroaldol reaction was carried out in
presence of only ionic liquid with no chiral ligand and
copper acetate the reaction at all does not occur (entry 17).
Under the optimized reaction condition (Table 1, entry
13) we further explored the efficacy of the in situ generated
complexes derived from chiral ligands 20–40 (12 mol.%)
and Cu(OAc)2ꢀH2O (10 mol.%), in the nitroaldol reaction
of benzaldehyde as representative substrate in [emim]BF4
as ionic liquid at 0 °C (Table 2, entries 1–4). The results
clearly indicate that bidentate ligands 10 and 20 (entries 1,
2) fared better in terms of product yield (82–84%) and ee
(86–88%) than tetradentate ligands 30 and 40 (entries, 3, 4;
yield, 23–36%; ee, 11–38%). A possible reason for this
Further, the isolated complex (10 mol.%) as synthesized
by the reaction of ligand 10 with Cu(OAc)2ꢀH2O, was tested
for its efficacy in the nitroaldol reaction of benzaldehyde
under the above optimized reaction condition (as per entry
13). The result showed a decrease in product yield (40%)
however the enantioselectivity (ee, 84%) was retained
(entry 14). This result is in consonance with the earlier
report [75]. The blank experiment conducted in the absence
of chiral ligand 10 keeping other conditions as per entry 13
yielded 52% racemic nitroalcohol (entry 15) indicates that
copper metal is active for nitroaldol reaction but to impart
enantioselctivity in the product a chiral ligand is essential.
123

194
N. H. Khan et al.
Table 2 Effect of chiral Cu(II) complexes generated in situ using the chiral ligands (10–40) for asymmetric nitroaldol reaction in presence of the
Ionic Liquid [emim]BF4
O
OH
1'-4'
Cu(OAc)2.H2O (10 mol%) /
(12 mol%)
NO2
CH3NO2
H
+
[emim]BF4, EtOH
Entry
Ionic liquid
Ligand
T (°C)
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
10
20
30
40
0
0
0
0
30
30
30
30
82
84
36
23
86
88
38
11
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of in situ generated complexes 1–4
a
from ligand 10–40(12 mmol and Cu(OAc)2ꢀ2H2O (10 mol.%) in 0.125 mL of solvent and 250 mg ionic liquid at 0 °C. Isolated yields by the
b
column chromatography. Determined by HPLC on a OD-H column
behaviour can be the ready access of catalytically active
metal centre to the reactants in the case of bidentate ligands
than relatively more rigid tetradentate ligands 30 and 40.
Moreover, mechanistically it is reported that in order to
show high activity and enantioselectivity the two reactants
should position themselves parallel to each other while
coordinating to the catalytically active metal centre [34].
The possibility of such an alignment is relatively higher in
the case of bidentate/tridentate ligands than in tetradentate
ligands due to steric and electronic considerations [61].
The above optimized reaction protocol for nitroaldol
reaction was further extended to various aromatic and
aliphatic aldehydes using the in situ generated complex
(having 12 mol.% ligand 20 and 10 mol.% Cu(OAc)2ꢀH2O
in the presence of [emim]BF4 as represented ionic liquid
and data is given in Table 3. Overall, all the substrates
used in the present study showed only marginal difference
in the ee and yield of the products chiral b-nitroalcohols
irrespective of the electron withdrawing (nitro) or electron
donating (OMe) substituents on the phenyl ring of alde-
hyde. Nevertheless, among all the substrate used here, the
best results in term of activity (yield, 89%) and enanti-
oselectivity (ee, 94%) (Table 3, entry 6) was achieved
with 4-methoxy benzaldehyde. The catalytic system also
worked well in terms of good yields and enantioselec-
tivity of nitroalcohol with aliphatic aldehyde (Table 3
entry 9).
Notwithstanding high reactivity and enantioselectivity,
the in situ generated complex (having 12 mol.% ligand 20
and 10 mol.% Cu(OAc)2ꢀH2O) in ionic liquid is recyclable
for the enantioselective nitroaldol reaction. To demonstrate
its recyclability, experiments were carried out by using
Table 3 Enantioselective nitroaldol reaction with various aldehydes catalyzed by in situ generated complex 2 in presence of ionic liquid
[emim]BF4
OH
2'
Cu(OAc)2.H2O (10 mol%) / (12 mol%)
O
NO2
CH3NO2
+
R
R
H
[emim]BF4, EtOH
Entry
R
Ligand
Ionic liquid
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
Ph
20
20
20
20
20
20
20
20
20
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
[emim]BF4
30
30
30
30
30
30
30
30
30
84
78
89
88
90
89
87
90
79
88
81
86
89
90
94
88
89
84
3-NO2Ph
4-NO2Ph
3-ClPh
4-ClPh
4-MeOPh
4-iPrPh
PhCH2CH2
C5H11
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of in situ generated complex 2 from
ligand 20 (12 mmol and Cu(OAc)2ꢀ2H2O (10 mol.%) in 0.125 mL of solvent 250 mg ionic liquid at 0 °C
Isolated yields by the column chromatography, Determined by HPLC on a OD-H column
a
b
123

Chiral Cu(II) Complexes as Recyclable Catalysts
195
Table 4 Recyclability test of the in situ generated catalyst 2 in presence of ionic liquid [emim]BF4
OH
2'
Cu(OAc)2.H2O (10 mol%) / (12 mol%)
O
NO2
CH3NO2
+
R
R
H
[emim]BF4, EtOH
Entry
Run
Ligand
T (°C)
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
5
1st
2
2
2
2
2
0
0
0
0
0
30
30
30
30
30
84
82
83
82
80
88
88
87
88
87
2nd
3rd
4th
5th
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of in situ generated complex 2 from
ligand 20(12 mmol and Cu(OAc)2ꢀ2H2O (10 mol.%) in 0.125 mL of solvent and 250 mg ionic liquid at 0 °C
Isolated yields by the column chromatography, Determined by HPLC on a OD-H column
a
b
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runs with marginal loss in yield. However, the enantiose-
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