Chiral Cu(ii)-amino alcohol based complexes for asymmetric aza-Henry reaction of N-Ts imines

Article abstract of DOI:10.1039/c3cy00774j

A series of chiral dimeric ligands 1A-C, 2A-B, 3A-B and 4A derived from (S)/(R) 1,1′-bi(2-naphthol)-bis-aldehyde/piperazine-bis-aldehyde and various aminoalcohols viz., (1R,2S)-(-)-2-aminodiphenylethanol, (1S,2R)-(-)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and (R)-valinol were synthesized. In situ generated complexes 1A-C-, 2A-B-, 3A-B-, 4A-Cu(ii)/Cu(i) of dimeric chiral ligands with different copper salts were used as catalysts for the asymmetric aza-Henry reaction of a variety of N-tosylimines as substrates with different nitroalkanes at RT to afford good yields of aza-Henry products (80% with respect to the imines) with excellent enantioselectivity (ee > 99%) in 24 h with nitromethane and high syn selective products with excellent enantioselectivity with nitroethane. The dimeric chiral Cu(ii) complex 1A-Cu(ii) retained its performance at the gram level and was expediently recycled for a number of times. The enantio-pure aza-Henry product was further used for the synthesis of (S)-levamisole (an anthelminthic agent) in good yield and ee in three steps. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cy00774j

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Chiral Cu(II)-amino alcohol based complexes for
asymmetric aza-Henry reaction of N-Ts imines†
Cite this: Catal. Sci. Technol., 2014,
4, 548
Manoj K. Choudhary,ab Anjan Das,ab Rukhsana I. Kureshy,
Manish Kumar,ab
ab
*
Noor-ul H. Khan,ab Sayed H. R. Abdiab and Hari C. Bajajab
A series of chiral dimeric ligands 1A–C, 2A–B, 3A–B and 4A derived from (S)/(R) 1,1′-bi(2-naphthol)-
bis-aldehyde/piperazine-bis-aldehyde and various aminoalcohols viz., (1R,2S)-(−)-2-aminodiphenylethanol,
(1S,2R)-(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and (R)-valinol were
synthesized. In situ generated complexes 1A–C–, 2A–B–, 3A–B–, 4A–Cu(II)/Cu(I) of dimeric chiral ligands with
different copper salts were used as catalysts for the asymmetric aza-Henry reaction of a variety of
N-tosylimines as substrates with different nitroalkanes at RT to afford good yields of aza-Henry products
(80% with respect to the imines) with excellent enantioselectivity (ee > 99%) in 24 h with nitromethane and
high syn selective products with excellent enantioselectivity with nitroethane. The dimeric chiral Cu(II)
complex 1A–Cu(II) retained its performance at the gram level and was expediently recycled for a
number of times. The enantio-pure aza-Henry product was further used for the synthesis of (S)-levamisole
(an anthelminthic agent) in good yield and ee in three steps.
Received 4th October 2013,
Accepted 4th November 2013
DOI: 10.1039/c3cy00774j
www.rsc.org/catalysis
with various metals (Cu, Zn, La, Ni, Yb)29–39 and organo-
catalysts40–54 have shown good catalytic activity in asymmetric
Introduction
The aza-Henry, or nitro-Mannich, reaction is a fundamental
C–C bond forming reaction in organic chemistry that involves
the addition of nitroalkanes to several types of imines. Nowa-
days, this reaction has drawn much attention, because the end
products of the aza-Henry reaction can easily be transformed
into many value added products viz., vicinal diamines via
reduction of the nitro group1,2 and α-amino carbonyl
compounds by the Nef oxidation.3–6 Several natural products
comprising of vicinal diamine moieties have valuable
biological7 and medicinal properties8 like antiarrhythmic,9
antidepressant,10 antihypertensive,11 analgesic,12 anticancer,
antiviral drugs13 and antiparasitic agents.14 Apart from the
applications in the field of medicinal chemistry, the use of
diamines has also gained considerable interest in the synthesis
of ligands for metal based catalysts15–19 and organo-catalysts.20–22
Due to the extensive applications of the enantio-pure product
of the asymmetric aza-Henry reaction, several catalytic
systems based on both metal and metal-free (organo-catalyst)
have been explored in recent years.23 Among them, BINOL,24,25
bis-oxazolines,26,27 phenyl bis oxazoline28 and salen ligands
aza-Henry reactions both in terms of yield and enantio-
selectivity at lower temperature, but there is a nagging issue of
separation and recycling of the catalyst. Chiral catalysts are very
expensive; hence their recyclability is of prime concern in off-
setting the catalyst cost. Consequently, we report here a couple
of modifications in the catalyst design. First, in order to
improve the efficiency two catalytic sites were incorporated in
one and thereby increase the molecular weight of the catalyst
to facilitate its recyclability.37,38 Second, incorporate basic sites
in the catalyst which might assist abstraction of the proton
from nitromethane to generate a nitronate ion as a nucleo-
phile. Finally, often an extra element of chirality helps in
improving enantioselectivity as demonstrated earlier in the
C–C bond forming reaction.55 Accordingly, we incorporated the
above features and prepared dimeric ligands 1A–C, 2A–B, 3A–B
and 4A, where chiral salen units are suitably linked through
chiral (R)/(S)-BINOL as an extra element of chirality or through
the piperazine group as base functionality by following simple
synthetic steps. The chiral dimeric complexes 1A–C–, 2A–B–,
3A–B– and 4A–Cu(II)/Cu(I) were generated in situ derived from
ligands 1A–C, 2A–B, 3A–B and 4A, respectively, with different
copper salts and examined their catalytic efficacy in aza-Henry
reaction for a wide range of N-tosylimines with various nitro-
alkanes notably at RT. Chiral β-nitroamines were obtained in
high yield and enantioselectivity particularly with the catalyst
generated from ligand 1A and copper acetate henceforth desig-
nated as 1A–Cu(II). The complex 1A–Cu(II) was easily isolated
a Discipline of Inorganic Materials and Catalysis, Central Salt and Marine
Chemicals Research Institute (CSIR-CSMCRI), Bhavnagar, 364 002, India.
E-mail: rukhsana93@yahoo.co.in; Fax: +91 0278 2566970
b Academy of Scientific and Innovative Research (AcSIR), CSIR-CSMCRI,
Bhavnagar, Gujarat-364021, India
† Electronic supplementary information (ESI) available: 1H & 13C-NMR data,
HPLC profiles of aza-Henry product. See DOI: 10.1039/c3cy00774j
548 | Catal. Sci. Technol., 2014, 4, 548–555
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from the catalytic mixture and recycled effectively up to five
cycles. This protocol was also applied for the synthesis of
anthelminthic (S)-levamisole56,57 at 1.0 g scale.
generates a more active catalyst (yield 80% and ee 90%;
Table 1, entry 1) than complexes of 1B–C–, 2A–B–Cu(II) having
other permutations and combinations of aminoalcohols with
(R)-BINOL/(S)-BINOL/piperazine as the chiral/achiral linker
(entries 2–5). Such an effect of matching and mismatching of
the chirality of an element, though not well understood, does
exist in literature.55 To further improve the activity of the pres-
ent catalytic system, other aminoalcohol functionalities with
one and two chiral centres viz., (1R,2S)-1-amino-2,3-dihydro-
1H-inden-2-ol and (R)-valinol with both (R)-BINOL/(S)-BINOL as
a chiral linker, referred as complexes 3A–B–, 4A–Cu(II) were
used in aza Henry reaction, however, the yield and ee of the
product declined sharply (entries 6–8). To assess the probable
role of diverse stereogenic centers in the catalyst that govern
the configuration of the product, CD spectra were recorded in
THF for in situ generated complexes viz., 1A–Cu(II), 2A–Cu(II)
and 1B–Cu(II) (Fig. 1). The complexes 1A–Cu(II) and 1B–Cu(II)
derived from (R)-BINOL and (S)-BINOL, respectively, with a
(1R,2S)-(−)-2-aminodiphenylethanol collar showed n → π* and
d → π* bands at 400 and 650 nm with negative cotton effect
and favored the (S) product formation (Table 1; entries 7
and 8). Whereas, the complex 2A–Cu(II) having (R)-BINOL
with (1S,2R)-(−)-2-aminodiphenylethanol showed n → π*and
d → π* bands with a positive cotton effect in the same
region and preferred the product with opposite configuration
(R) (Table 1, entries 5 and 6). Based on these results it can
be assumed that the enantio-induction in the product of the
aza-Henry reaction of N-tosylimines 2b is largely governed by
the chirality originated from aminoalcohol functionality, but the
Results and discussion
In the quest of developing a highly active and enantio-
selective catalyst for aza-Henry reaction, new chiral dimeric
ligands 1A–C, 2A–B and 4A were prepared by the condensa-
tion of a bis-aldehyde having linker A, B, or C with various
aminoalcohol viz., (1R,2S)-(−)-2-aminodiphenylethanol,(1S,2R)-
(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-
inden-2-ol and (R)-valinol (Scheme 1). Meanwhile chiral
dimeric Schiff base ligands 3A and 3B were prepared by
the reaction of bis-aldehyde having linker A or B with
(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol by the reported
method.58 The catalytic activity and selectivity of catalysts
generated in situ with the ligands 1A–C, 2A–B, 3A–B and
4A (10 mol%) with Cu(OAc)2·H2O (15 mol%) as a metal
source and N-tosylimine 2b as the substrate in toluene
with nitromethane as the nucleophile at room temperature
and data are summarized in Table 1. In the first set
of screening of complexes of 1A–C, 2A–B–Cu(II) we
altered the linker namely, (S)-BINOL/(R)-BINOL (chiral) and
piperazine (achiral) at 5,5′-positions of the dimeric ligands,
with (1R,2S)-(−)-2-aminodiphenylethanol and a (1S,2R)-(−)-2-
aminodiphenylethanol collar. We observed that the dimeric
complex 1A–Cu(II) having a (1R,2S)-(−)-2-aminodiphenylethanol
collar with (R)-BINOL as the linker (matching chirality element)
Scheme 1 Synthesis of chiral dimeric Schiff bases.
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Table 1 Screening of in situ generated chiral salen complexes with ligands 1A–C, 2A–B, 3A–B and 4A and Cu(OAc)2·H2O as a source of metal used
with nitromethane at RTa
1A
1B
2A
2B
Entry
Yieldb (%)
80
eec (%)
Entry
Yieldb (%)
74
eec (%)
Entry
Yieldb (%)
77
eec (%)
Entry
Yieldb (%)
73
eec (%)
54
1
90(S)
2
60(S)
3
80(R)
4
1C
3A
3B
4A
Entry
Entry
Yieldb (%)
59
eec (%)
30
Entry
Yieldb (%)
65
eec (%)
40
Entry
Yieldb (%)
56
eec (%)
22
Yieldb (%)
42
eec (%)
30
5
6
7
8
a
All the reactions were performed with 2b (0.2 mmol), nitromethane (5.0 mmol), ligands 1A–C, 2A–B, 3A–B and 4A (0.02 mmol), Cu(OAc)2·H2O
b
c
(0.03 mmol) in toluene for 24 h. Isolated yields after flash column chromatography. Determined by HPLC (Chiralcel OD-H). Absolute
configuration of the product was determined by compairing the HPLC profile and optical rotation value with reported literature data.
of the corresponding aza-Henry product. To further
confirm the role of the chiral BINOL linker in the cata-
lytic aza-Henry reaction and to explore
a comparative
study of 1A–Cu(II) with a chiral monomeric Schiff base
complex, the monomeric ligand was synthesised by the
interaction of (1R,2S)-(−)-2-amino-1,2-diphenylethanol with
3,5-di-tert-butylsalicylaldehyde. In situ generated monomeric
complex from monomeric ligand with Cu(OAc)2·H2O in
1 : 1 molar ratio was used as a catalyst in the asymmetric
aza-Henry reaction of 2b with nitromethane under the same
reaction conditions which gave 45% yield of aza-Henry
product with 74% ee in 24 h. However, 1A–Cu(II) gave 80%
yield of aza-Henry product with 90% enantioselectivity under
similar reaction conditions, inferring the significant role of
BINOL in the present catalytic system. Further, the present
catalytic system gave comparable results under milder reac-
tion conditions (RT) as compared to the reported Schiff base
systems with different metal ions where the catalytic systems
need a very low reaction temperature (0 to −40 °C).59
Fig. 1 CD spectra of Cu(II) complexes generated in situ derived from
1A, 1B, 2A ligands in THF.
BINOL linker with matching chirality element also imparts
a positive effect on catalytic activity and enantioselectivity
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Table
3
Screening of solvent, catalyst loading and reaction
Invariably, in the asymmetric version of this reaction, the
counter ions of the metal salt play an imperative role. Therefore,
the dimeric ligand 1A (most active and enantioselective) at
10 mol% loading in combination with a wide range of copper
salts having different counter ions like Cl−, OAc−, OTf−, I− were
screened for their effectiveness in the aza-Henry reaction of 2b
with nitromethane at RT in toluene as a solvent. Among these,
Cu(OAc)2·H2O was found to be the most effective (ee, 90%; yield,
80%; Table 2, entry 2). Since the counter ion of the metal source
helps to abstract the proton from the nitroalkane to generate
active nucleophile, the basicity of the same is a key factor for
the asymmetric aza-Henry reaction. Among the three Cu(II) salts
with different counter ions, the basicity order is (OAc− > OTf− >
Cl− > I−) and the yield of the product also follows the same
order,36 except for CuI which showed no catalytic activity possibly
due to the formation of a complex with unfavourable geometry.
In order to improve the yield and enantioselectivity of chiral
β-nitroamines, the catalyst 1A–Cu(II) (most promising among
screened) was subjected to optimization of catalytic reaction
parameters like solvents, reaction temperature and catalyst
loading. Since solvents have a decisive role in asymmetric
reactions, so it was necessary to choose a suitable solvent for
this reaction. A range of solvents like CH3Cl, CH2Cl2, benzene,
toluene and THF (Table 3, entries 1–7) were varied for the
asymmetric aza-Henry reaction of 2b with nitromethane at RT.
From the results of Table 3, it is clear that the non-polar
solvents are more suitable than polar solvents in terms of
both selectivity and activity and among them the non-polar
toluene proved to be the best solvent (ee 90%, yield 80%,
Table 3, entry 5). Since catalyst loading also plays an impor-
tant role in achieving high yield and selectivity, hence this
reaction was carried out with different catalyst 1A–Cu(II) load-
ing, ranging from 2–12 mol% (Table 3, entries 5, 8–11).
temperature for the asymmetric aza Henry reaction of 2b using the
ligand 1A–Cu(II) with nitromethanea
Cat. loading
(mol%)
Entry Solvent
Temp (°C) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
CH3NO2 10
CH2Cl2
CHCl3
Benzene 10
Toluene 10
Xylene
THF
Toluene
Toluene
Toluene
Toluene 12
Toluene 10
Toluene 10
Toluene 10
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
40
40
30
25
75
80
72
42
30
62
65
80
85
54
35
45
15
20
90
90
75
35
61
75
69
68
67
56
50
10
10
10
10
2
5
8
9
10
11
12
13
14
0
−10
a
All the reactions were performed with 2b (0.2 mmol), nitromethane
b
(5.0 mmol), with ligand 1A and Cu(OAc)2·H2O in solvents. Isolated
yields after flash column chromatography. Determined by HPLC
(Chiralcel OD-H).
c
The temperature effect on this reaction was our next parameter
for the optimization study after we fixed the solvent, as toluene
and catalyst loading 10 mol%. In case of temperature optimiza-
tion, our initial reaction temperature RT (entry 5) turned out to
be the optimum as increasing or lowering the reaction temper-
ature (Table 3, entries 12–14) had adverse effects on product
yield and ee. To see the general applicability of the catalyst
1A–Cu(II), the above optimized reaction condition was applied
to the enantioselective aza-Henry reaction for a variety of
aromatic and aliphatic N-tosylimines 2a–k as a substrate hav-
ing electron donating (Table 4, entries 2–5) and withdrawing
(Table 4, entries 6, 7) substituents on the aromatic ring and
bulkier 1/2-naphthyl moieties (Table 4, entries 8, 9) with nitro-
methane. To our satisfaction, the catalytic system has demon-
strated good to excellent enantio-induction (ee, 86–>99%)
without much influence of substituents and their position
on the aromatic ring of the substrate, however there is
marginal effect on the product yield of their respective chiral
β-nitroamines (yield up to 80%). The use of nitroalkanes
other than nitromethane is less explored in the case of an
asymmetric aza-Henry reaction; hence, the present protocol
was tested for its efficacy in the aza-Henry reaction of
various aromatic N-tosylimines with nitroethane. Fortunately,
the catalytic system has demonstrated good to excellent
enantio-induction (ee, 45–>99%) without much influence of
substituents and their position on the aromatic ring of the sub-
strate, however there is a marginal effect on the product yield
of their respective chiral β-nitroamines (yield up to 80%).
Among these, the substrates with electron donating groups
It is clear from the Table 3 that with decreasing catalyst
loading, the enantioselectivity as well as activity of the reac-
tion declines. Further, an increase in the catalyst loading
beyond 10 mol% was of no advantage (Table 3, entry 11). So,
10 mol% catalyst was taken as ideal for the present system to
get the best result with ee 90% and yield 80%. (Table 3, entry 5)
Table 2 Screening of counter ions of the metal source for an asymmetric
aza-Henry reaction of 2b using the ligand 1A with different copper saltsa
Entry
Metal source
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
CuCl2·2H2O
Cu(OAc)2·H2O
(CuOTf)2·H20
CuI
10
24
20
5
30
80
60
—
35
90
50
—
a
All the reactions were performed with 2b (0.2 mmol), nitromethane
(5.0 mmol), ligand 1A (0.02 mmol), CuX2/CuX (0.03 mmol) in toluene.
b
c
Isolated yields after flash column chromatography. Determined by
HPLC (Chiralcel OD-H).
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Table 4 Variation of substrates in the asymmetric aza-Henry
reactiona
Entry
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5 (2a)
78 (3a)
80 (3b)
70 (3c)
78 (3d)
71 (3e)
80 (3f)
77(3g)
72 (3h)
79 (3i)
68 (3j)
75 (3k)
86
90
>99
90
89
>99
>99
89
99
99
2-MeO C6H5 (2b)
4-MeO C6H5 (2c)
2-Me C6H5 (2d)
4-Me C6H5 (2e)
2-F C6H5 (2f)
Fig. 2 A stepwise overlay of UV-vis spectra in THF solvent (a) ligand
(b) complex (c) complex, imine (d) complex, imine and nitromethane
after 1 h (e) complex, imine and nitromethane after 5 h (f) complex,
imine and nitromethane after 10 h (g) complex, imine and nitrometh-
ane after 15 h.
4-F C6H5 (2g)
1-Naphthyl C6H5 (2h)
2-Naphthyl C6H5 (2i)
C6H5CH2 (2j)
9
10
11
the complex itself. When nitromethane was added to this
solution, a transition state (TS) with hyperchromic shift was
observed which was decreased gradually with time due to the
release of the catalyst with product formation37 (Scheme 2).
Having established the aza-Henry parameters with catalyst
1A–Cu(II) the present protocol was extended to the synthesis
of chiral drug (S)-levamisole (an anthelminthic agent used to
treat parasitic worm infections in humans) at 1 g scale with
good yield and retention of enantioselectivity in three steps
(Scheme 3).
CH3(CH2)6CH (2k)
90
a
All the reactions were performed with 2a–k (0.2 mmol), nitromethane
(5.0 mmol), ligand 1A (0.02 mmol), Cu(OAc)2·H2O (0.03 mmol) in 0.6 ml
b
of toluene at RT for 24 h. Isolated yields after flash column
chromatography. c Determined by HPLC (Chiralcel OD-H, AD-H, IA, IC).
(Table 5, entries 2–4) gave the best results in terms of both
enantioselectivity and diastereoselectivity with syn as the major
diastereomer.
In addition to high reactivity and enantioselectivity in the
aza-Henry reaction, the catalyst 1A–Cu(II) is recyclable as
evidenced by the recycling experiments (Fig. 3). The recycla-
bility experiments were carried out by using 2b (2.0 mmol) as
a model substrate with nitromethane (5.0 mmol) as nucleo-
phile in toluene at room temperature using the complex
1A–Cu(II) (10 mol%) as a catalyst. After the completion of
the catalytic reaction, the catalyst was recovered quantitatively
and successfully recycled five times without any apparent loss
in activity and enantioselectivity (Fig. 3).
In order to understand the probable mechanism of the
catalytic asymmetric aza-Henry reaction, a stepwise overlay
of the UV-vis spectra were recorded in THF (Fig. 2). In case of
in situ generated Cu(II) complex 1A–Cu(II) two new bands
appeared at 622 nm (for d–d transition) and at 389 nm
(LMCT) confirming the complexation.
On addition of N-tosylimine to this complex, there was a
slight blue shifting (6 nm) in the LMCT band, possibly due to
the formation of an intermediate with little higher energy than
In order to investigate the stability of the recycled catalyst,
IR spectra of the recycled catalyst were recorded and com-
pared with the IR of the fresh catalyst (Fig. 4). From the
Table
5 Variation of substrates with nitroethane in asymmetric
aza-Henry reactiona
Eed (%)
Entry R1
Yieldb (%) Syn/antc
syn anti
1
2
3
4
5
6
C6H5 (2a)
82 (4a)
78 (4b)
72 (4c)
68(4e)
90/10
97/03
48/52
98/02
93/07
70/30
81
99
93
99
89
69
85
69
99
45
65
46
2-MeO C6H5 (2b)
4-MeO C6H5 (2c)
4-Me C6H5 (2e)
2-Naphthyl C6H5 (2i) 70 (4i)
2-Cl C6H5 (2l) 65 (4l)
a
c
All the reactions were performed with , 2e, 2i–l (0.2 mmol),
nitroethane (5.0 mmol), ligand 1A (0.02 mmol), Cu(OAc)2·H2O
b
(0.03 mmol) in 0.6 ML toluene for 24 h at RT. Isolated yields
c
Scheme
aza-Henry reaction.
2 A probable mechanism for the catalytic asymmetric
after flash column chromatography. Determined from NMR data.
d
Determined by HPLC (Chiralcel AD-H, OD-H, IA, IC).
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and yield. To find out the scalable property of catalytic
system, a gram level catalytic run demonstrated the synthesis
of (S)-levamisole (an anthelminthic agent for human) in
three steps.
Experimental section
General
Copper acetate monohydrate, copper triflate, copper chloride,
copper iodide, nitromethane, nitroethane, (1R,2S)-1-amino-
2,3-dihydro-1H-inden-2-ol, (R)-valinol, (R)-BINOL, (S)-BINOL,
(1R,2S and 1S,2R)-2-amino-1,2-diphenyoethanol and pipera-
zine anhydrous were purchased from Aldrich Chemicals
and used as received. (S)-5,5′-(1,1′-binaphthyl-2,2′-diylbis(oxy))
bis(methylene)bis(3-tert-butyl-2-hydroxybenzaldehyde)/(R)-5,5′-
(1,1′-binaphthyl-2,2′-diylbis(oxy))bis(methylene)bis(3-tert-butyl-
2-hydroxybenzaldehyde) and 5,5′-(piperazine-1,4-diylbis(methylene))
bis(3-tert-butyl-2-hydroxybenzaldehyde) were synthesized by our
reported procedure.58,60 N-Tosylimines were synthesized by the
reported method.61,62 All the solvents were dried by
standard procedures, distilled and stored under nitrogen.
1H NMR spectra were obtained with a Bruker F113V spectro-
meter (200 MHz) and are referenced internally with TMS FT-IR
spectra which were recorded on a Perkin Elmer Spectrum GX
spectrophotometer in a KBr window. High-resolution mass
spectra were obtained with a LC–MS (Q-TOFF) LC (Waters), MS
(Micromass) instrument. For the product purification, column
chromatography was performed using silica gel 60–200 mesh
purchased from s.d. Fine-Chem Limited Mumbai (India).
Enantiomeric excess (ee) of the products were determined
by HPLC (Shimadzu SCL-10AVP) using Daicel Chiralpak AD,
OD, AD-H, OD-H column with 2-propanol–hexane as eluent.
Optical rotations were measured with a Digipol 781 Automatic
Polarimeter Rudolph Instruments. UV-visible spectra were
recorded on a Shimadzu UV 3101 PC NIR spectrophotometer
(Japan). Circular Dichroism (CD) spectra were obtained by
using a JASCO J-815 CD spectrophotometer (Japan).
Scheme 3 Synthetic route to produce (S)-levamisole.
Fig. 3 Recyclability study of the catalytic system for the asymmetric
aza-Henry reaction.
Synthesis of ligands (1A–C, 2A–B, 3A–B, 4A)
Fig. 4 IR spectra of fresh catalyst and recycled catalyst after 5 cycles.
Bis aldehydes, namely, (S)-5,5′-(1,1′-binaphthyl-2,2′-diylbis(oxy))
bis(methylene)bis(3-tert-butyl-2-hydroxybenzaldehyde)/(R)-5,5′-
(1,1′-binaphthyl-2,2′-diylbis(oxy))bis(methylene)bis(3-tert-butyl-
2-hydroxybenzaldehyde) and 5,5′-(piperazine-1,4-diylbis(methylene))
bis(3-tert-butyl-2-hydroxybenzaldehyde) (2 mmol) were dissolved
in dry THF (50 ml) to which two equivalent of (1R,2S or 1S,2R)-
2-amino-1,2-diphenylethanol/(1R,2S)-cis-1-amino-2-indanol/(R)-
valinol (4 mmol) was added slowly under a nitrogen atmo-
sphere. The resulting solution was stirred for 4 h at room
temperature and the reaction was monitored by TLC. After
completion of the reaction, the solvent was partially removed
from the reaction mixture on a rotary evaporator that gave a
yellow precipitate. The solid obtained after filtration was
washed with hexane : DCM (50 : 1) to get the yellow colored
desired ligands 1A–C, 2A–B, 3A–B and 4A. The characterization
data of all the ligands are given in the ESI.†
spectra it was clear that there is no change in the structure of
the complex after the recycling study.
Conclusion
In conclusion, we have designed a series of chiral dimeric
ligands derived from (S)/(R) 1,1′-bi(2-naphthol)-bis-aldehyde
and piperazine-bis-aldehyde as linkers with various amino-
alcohol functionalities for the asymmetric aza-Henry reaction
of different N-tosylimines having both electron donating and
withdrawing substituents on the aromatic ring with nitro-
alkanes giving both very good to excellent enantioselectivity
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Catalysis Science & Technology
Typical experimental procedure for the asymmetric
aza-Henry reaction
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