Cinchona alkaloid-based chiral catalysts act as highly efficient multifunctional organocatalysts for the asymmetric conjugate addition of malonates to nitroolefins

Article abstract of DOI:10.1039/c5ob01351h

New pentaerythritol tetrabromide-based chiral quaternary ammonium salts acting as organocatalysts (7a and 7b) have been prepared and used as organocatalysts for enantioselective Michael addition reactions between various nitroolefins and Michael donors (malonates) under mild reaction conditions, such as lower concentration of base and catalyst and room temperature, with very good chemical yields (up to 97%) and ee's (up to 99%).

Full text of DOI:10.1039/c5ob01351h

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Cinchona Alkaloid Based Chiral Catalysts act as Highly Efficient
Multifunctional Organocatalyst for the Asymmetric Conjugate
Addition of Malonates to Nitroolefins
Veeramanoharan Ashokkumar and Ayyanar Siva*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Abstract: New type of pentaerythritol tetrabromide based chiral quaternary ammonium act as organocatalysts 7 (7a and
7b) have prepared and used as organocatalysts for enantioselective Michael addition reactions between the various
nitroolefin and Michael donors (malonates) under mild reaction conditions such as lower concentration of base, catalyst
and room temperature with very good chemical yields (up to 97%) and ee’s (up to 99).
www.rsc.org/
Introduction
Michael addition of nitroolefins, their full potential is not yet to be
reached or explained in terms of both enantioselectivity and
general applicability. Both the previous reports were used higher
concentration of catalyst loading 10 mol% and 20 mol% and longer
reaction time (24-40h). Previously, we reported a series of tri-
functional mesitylene and triazine based cinchona alkaloids as a
chiral phase transfer catalysts (CPTC) for highly enantioselective
Michael addition reactions of chalcones with very good yield and
ee’s.26 In this work is also the extending of our research interest of
the organocatalyst in asymmetric catalysis and also first time we
report the tetrafunctional organocatalysts for effective
enantioselective Michael addition reaction under mild reaction
conditions such as catalyst loading (1 mol%) and time (30 mins) at
room temperature conditions.
In recent organic synthesis, most of the researchers were
concentrated new smart design, practical, cost-effective and
environmental friendly catalytic systems.1 In particularly synthesis
and optimisation of chiral organocatalysts were very much needed
to achieve highly enantioselective controlled optically active
enantiopure products with very good yield.2-3 Generally, there are
many types of organocatalyst available for the synthesis of efficient
enantiopure products which includes chiral catalyst such as
5
proline,4 cinchona alkaloids via quinine, cinchonine, and various
8a
sugar,6 amino acid,7 ionic liquid or amide-derived compounds.8b
Asymmetric synthesis, available in great varieties, were the vital
source of a large number of chiral compounds that have become
essential for human society.9
Among these enantioselective asymmetric Michael addition
reaction of electron deficient olefins, particularly α, β-unsaturated
ketones such as chalcone, nitroolefins, have been investigated and
reported lower to moderate yield and ee’s under organocatalysts
and phase transfer catalysts (PTC).10-23 In this connection Lee et. al.,
F3C
N
H
N
NH
N
NH
N
N
H
N
H
CF3
H
1a
1b
have been
reported the 2-aminobenzimidazole bifunctional
O
O
N
organocatalyst 1a and 1b with the commercially available diethyl
malonate as Michael donor at 0°C to RT for the effective Michael
addition of nitroolefins in the presence of 10 mol% of catalyst with
better yields (82-99%) and ee's (90-93%).24a Consecutively, Suez et
al.,24b reported the enantioselective Michael addition of nitroolefins
in the presence of 20 mol% of quanine based organocatalyst 2a and
2b at room temperature but the reaction was carried out longer
time (24-144 h) with moderate yield (41-94%) and ee’s (84-88%).
Even though there are numerous reports25 available for
enantioselective
NH
NH
NH
NH
F3C
N
F3C
NMe2
NMe2
2a
2b
Fig. 1 Previously reported chiral organocatalysts
Here, we focused on the enantioselectivity and the chemical
yield of Michael addition of nitroolefins reactions (Scheme 1) using
new types of tetra functional organocatalysts derived from
cinchonine 6 under mild reaction conditions. Here, we synthesized a
new series of tetrafunctional organocatalyst using pentaerythritol
tetrabromide as a core.27 In this work, we reported very good yield
(up to 97%) and excellent ee’s (up to 99%) at ambient temperature
conditions.
a.Department of Inorganic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai-625 021, Tamil Nadu, India. E.mail. drasiva@gmail.com
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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(Scheme 2). The pentaerythritol tetrabromide based chiral
multifunctional organocatalysts ((CMOCs) (7a and 7b)) were
synthesized from the reaction of tetrabromide 5 with cinchonine
free C9-OH 6a and O- allylcinchonine 26 6b respectively as depicted
in scheme 3.Thus, an initial attempt was made by treating
nitroolefin (8) with diethyl malonate (9) in the presence of different
chiral organocatalysts (COCs) 1, 2 and CMOCs 7 (1 mol%) in ethanol
at room temperature. This revealed that 1, 2 are indeed able to act
as catalyst, though its activity and stereoselectivity is insufficient
even increased the reaction time from 12 to 144 hrs (entry 1-4 in
Table 1). But our newly synthesized CMOCs 7a and 7b influenced
the reaction rate and we got very good yield upto 96% and ee’s
upto 99% (entries 5 and 6, Table 1) under same conditions with
lesser time (only 30 min). This is due to the multiactive sites are
present in the catalysts 7 and ion pair interaction is more with the
catalysts and the anions of the Michael donor. Further, we believe
that the simultaneously cooperative neigboring group of the
cinchonium cation with the Michael donors.
Results and discussion
Scheme
1 Synthesis of Enantioselective Michael addition of
Nitroolefins with various Michael donors.
Table 1 Catalytic asymmetric Michael addition reaction of diethyl
malonate 9 to nitroolefin 8 with different COCs 1, 2 and CMOCs 7
(7a/ 7b) in room temperature.
Scheme 2 Synthesis of Scaffold 5.
N
N
HO
H
OH
H
N
Entry
Catalysts
Time
(hours) a
6
Yield
ee %
Abs.
N
OH
H
O
O
O
O
b
c
Conf d
N
N
%
6a
1
2
3
4
5
6
1a
1b
2a
2b
7a
7b
45
99
94
33
96
96
78
93
84
45
99
99
R
R
R
R
R
R
EtOH:DMF:ACN
(30:50:20)
OH
N
4Br
7a
N
24
OH
Reflux
Overnight
N
H
H
24
N
144
0.5
5
0.5
N
O
N
H
a
N
The Michael reaction of Nitroolefin 8 (0.067 mmol), diethyl
H
O
O
O
O
N
THF:ACN (1:1)
O
malonate 9 (0.073 mmol), COCs (1a, 1b, 2a, 2b) CMOCs 7 (7a/7b, 1
Reflux
Overnight
mol%), with 1 ml of ethanol and triethylamine (0.073 mmol) in
O
N
4Br
b
c
N
room temperature.
Isolated yield of purified material.
O
N
H
N
H
O
Enantiopurity was determined by HPLC analysis of the Michael
adduct 10 using a chiral column (Chiralcel OD-H) with hexane-IPA as
an eluent. d Absolute configuration was determined by comparison
of the HPLC retention time.12b
H
7b
N
N
6b
Scheme 3 Synthesis of CMOCs 7 (7a and 7b).
Further, we carried out the optimization of bases for Michael
addition of Nitroolefin 8 with diethylmalonate 9 in the presence of
CMOCs 7 under identical reaction conditions. From that results, we
observed that the triethylamine, DIEA are the more effective bases
than the other bases such as pyridine, piperidine, KtOBu, Cs2CO3,
K2CO3, (entries 1-14 in Table 2).
The tetraester 3, obtained from the modified procedure27 of the
four fold O-alkylation of pentaerythritol tetrabromide with methyl-
4-hydroxybenzoate, then it was reduced with LiAlH4 in THF to afford
the tetra-alcohol 4 with 90% yield. Further, the tetraalcohol 4 was
treated with HBr in CH3COOH to give tetrabromide 5 with 92% yield
2 | J. Name., 2012, 00, 1-3
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Table 2 Effect of bases in the Michael addition reaction in the Through extensive screening, the optimized reaction conditions are
presence of the nitroolefin 8 and diethyl malonate 9 with CMOCs 7 found to be 1 mol % of catalyst 7, triethylamine as base and ethanol
(7a/7b), under room temperature.
as solvent at room temperature.
Table 3 Effect of solvents in the Michael addition reaction of
nitroolefin 8, diethyl malonate 9, CMOCs 7 (7a/7b), under room
temperature.
Ent Base
ry
Cataly
st
Time
Yield
(%)b
% of
eec
Abs.
(min)a
conf.d
1
2
3
4
5
6
7
8
9
KtOBu
KtOBu
K2CO3
K2CO3
CS2CO3
CS2CO3
TEA
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
70
70
60
60
50
50
30
30
40
40
60
60
60
60
80
83
84
85
86
86
87
99
99
89
90
71
73
71
73
R
Ent
ry
Solvents
Catalyst
Time
Yield
%
%
of
Abs.
80
90
90
93
93
96
96
95
95
75
75
70
70
R
R
R
R
R
R
R
R
R
R
R
R
R
b
(min)a
conf.
d
ee
c
1
2
3
4
5
6
7
8
9
Methanol
Methanol
Ethanol
Ethanol
Acetone
Acetone
DCM
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
35
35
30
30
40
40
50
50
50
50
55
55
60
60
95
95
96
96
88
88
86
86
80
80
70
70
65
65
99
99
99
99
89
90
84
88
83
86
83
85
82
83
R
R
R
R
R
R
R
R
R
R
R
R
R
R
TEA
DIEA
10 DIEA
11 Pyridine
12 Pyridine
13 Piperidine
14 Piperidine
DCM
CHCl3
10 CHCl3
11 THF
12 THF
13 Toluene
14 Toluene
a
The Michael reaction of nitroolefin 8 (0.067 mmol), diethyl
malonate 9 (0.073 mmol), CMOCs 7 (7a/7b, 1 mol%), with 1 ml of
ethanol and various bases (0.073 mmol) in room temperature.
Isolated yield of purified material. Enantiopurity was determined
by HPLC analysis of the Michael adduct 10 using a chiral column
(Chiralcel OD-H) with hexane-IPA as an eluent.
configuration was determined by comparison of the HPLC retention
time.12b
b
c
a
The Michael reaction of nitroolefin 8 (0.067 mmol), diethyl
malonate 9 (0.073 mmol), CMOCs 7 (7a/7b, 1 mol%), with 1 ml of
various solvents and triethylamine (0.073 mmol), in room
temperature. Isolated yield of purified material. Enantiopurity
was determined by HPLC analysis of the Michael adduct 10 using a
chiral column (Chiralcel OD-H) with hexane-IPA as solvents.
d
Absolute
b
c
d
Then the asymmetric Michael addition reaction was carried out
in different solvents using CMOCs 7 (7a and 7b) under room
temperature, the other parameters are kept as constant. The
obtained results (Table 3) show that, the change of solvent is found
to be an important crucial factor in the Michael addition reaction
due to their polarity of the solvents. The product yield and ee’s
have been found to decrease gradually, using polar to nonpolar
solvents (entries 1-14, Table 3), among solvents THF and toluene
mediated reactions are reduced the activity of 7a and 7b resulted in
poor yield and ee’s of Michael adduct 10 (entries 11-14, Table 3).
Further, we get moderate yields and ee’s of 10 using aprotic
solvents such as acetone, chloroform and DCM (entries 5-10, Table
3) and we found very good yield and ee’s of 10 when we are using
protic polar solvents such as methanol and ethanol. (entries 1-4,
Table 3). The optimization of the Michael addition reaction of
nitroolefin 8 with diethyl malonate 9 was carried out in the
presence of different reaction temperature conditions. From the
observed results, higher chemical yield and ee’s are obtained at
room temperature when compared with other temperature
conditions (i.e. -10 °C, ultrasonic and 50 °C) (entries 1-8, Table 4).
Absolute configuration was determined by comparison of the HPLC
retention time.12b
Further, the catalytic efficiencies were studied by the Michael
addition reaction of various nitroolefins 8(a-e) and Michael donors
9(a-c) under the optimized reaction conditions described above (1
mol% of the catalysts 7a or 7b, triethylamine, ethanol, room
temperature). From the observed results in table 5, independent of
the substitution on the aryl group of the nitroolefins, both the
electron withdrawing and electron donating groups are present on
the aryl groups which could not affect the product yield and ee's,
we found an excellent yields and ee’s (entries 1-30, Table 5).
Table 4 Optimization of asymmetric Michael addition between the
nitroolefin 8 and diethyl malonate 9 with CMOCs 7 (7a/ 7b) in
various
conditions.
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power (electrophile attracting power) towards the anions of
nitroolefin. As a result, the formation of degree of ion-pair between
R4N+ of tetra-site CMOCs (7a and 7b) with anions of the nitroolefin
is relatively lower hence we got moderate yield and ee's.
Entr Catal Conditi
Time
(hrs)a
Yield
%
% of
ee c
Abs.
b
y
yst
on
conf d
1
2
3
4
5
6
7
8
7a
7b
7a
7b
7a
7b
7a
7b
USe
USe
10
10
6
85
86
65
68
75
77
96
96
71
73
73
73
88
88
99
99
R
R
R
R
R
R
R
R
500 C
500 C
-100C
-100C
RT
N
N
5
H
8
O
H
O
OMe
N
9
N
N
O
N
O
0.5
0.5
O
O
O
O
H
MeO
O
O
OMe
O
RT
H
O
4Br-
HO
N
N
O
O
O
a
OMe
The Michael reaction of Nitroolefin 8 (0.067 mmol), diethyl
H
H
malonate 9 (0.073 mmol), CMOCs 7 (7a/7b, 1 mol%), with 1 ml
ethanol and triethylamine (0.073 mmol) in various conditions.
Isolated yield of purified material
N
b
c
N
Enantiopurity was determined
Fig. 2 Ion-pair interaction between the R4N+ of CMOCs with anion of
the substrate via co-operative influenced due to electrostatic
attractions.
by HPLC analysis of the Michael adduct 10 using a chiral column
d
(Chiralcel OD-H) with hexane-IPA as solvents.
Absolute
configuration was determined by comparison of the HPLC retention
time.12b e Ultrasonication
Further, from the established optimized reaction conditions for
Further, the formation of the yield and ee’s of Michael adduct
the model reaction, the scope of this Michael addition was studied 10 in the presence of C9(O) protected CMOCs such as cinchonine
and the results were listed in Table 5. From the observed results, derived
(entries 1-14, Table 2) is purely based on the
7
almost all the substituted β-nitroalkenes bearing either electron-
donating or withdrawing substituents on the aromatic ring gave the
stereochemistry/molecular assembly of CMOCs with substrates.
That is, in general irrespective of C9 free OH or C9 (O) protected
desired Michael adducts in very good yields (up to 97%) and good CMOC’s, there should be three factors which influence chemical
enantioselectivities (89-95%) (entries 7-30, Table 5). Unsubstituted
yield and ee’s: (i) effective contacts of ion-pair formed between
R4N+ of CMOC’s with anion of nitroolefin (ii) with the same ion-pair
β-nitroalkenes gave better enantioselectivity compared with
substituted β-nitroalkenes bearing electron-withdrawing or interaction of the enolate of the diethylmalonate with R4N+ of
electron-donating groups in the aromatic ring (entries, 1-6, Table 5). CMOC’s (iii) intermolecular hydrogen bonding between C9 free -OH
When 2-(nitrovinyl)-benzene used highest yield (97%) and excellent
of CMOC’s with anions of nitroolefin and
α-carbon of
enantioselectivity (99% ee) is achieved irrespective of the catalysts
diethylmalonate. We strongly believed that the above three
possible electrostatic processes are responsible for deciding the
yield 10 and ee’s.28
7a or 7b (entries, 5 and 6, Table 5). The formation of higher
chemical yield and ee’s for C9 (O) protected CMOC 7b is due to the
presence of effective formation of contact ion-pair between the
R4N+ of CMOCs with anion of the substrate via co-operative
influenced by close spatial arrangement of two active-site (Fig 2).
Further, the formation of lower/moderate yield and ee’s in the
Michael addition of nitroolefin due to the electronic effect. That is,
as we observed in tetra-site based CMOCs 7 (7a and 7b) contain
lone-pair of electrons on the oxygen atoms (present in each corner
of pentaerythritol) shift the electron density to the electron
deficient terminal R4N+ site of the CMOCs via aromatic ring spacer
chain, as a result no bond resonance is formed (Fig 3). This leads to
detachment/deactivation of catalytic site, thus lose their attracting
In the reaction, on deprotonation of the
α-carbon of the
diethylmalonate 9 by the triethylamine, the -carbon anion of the
α
diethylmalonate is generated which in turn forms an ion pair with
the R4N+ of the CMOCs and a subsequently negative charge is
developed on the enolate of the substrate leading to an ion-pair
with the R4N+ of the CMOC’s. These ion-pair formation brings the
substrates closer by reducing the bonding distance of R4N+ of
CMOC’s (Fig 4a). Subsequently, there is the possibility for hydrogen
bonding through the same electrostatic attraction between the
anion of
α-carbon of diethylmalonate with C9 free -OH of the
CMOC’s in turn prevents the movements of anionic substrate
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species towards R4N+ of the CMOC’s (Fig 4b). Whereas, in C9 (O) be more dominant and thus anionic substrate (nitroolefin) are
protected CMOCs catalysed reaction (entries 5-14 , Table 3 ), the moved very fast closer to R4N+ active site of CMOC’s without any
possibility for formation of hydrogen bond between the C9 free-OH
constraint and followed by further attraction of anion of α-carbon
with α-carbon anion of dimethylmalonate is completely unobserved of diethylmalonate with the nitroolefin facilitating higher order of
since the free –OH at C9 position is protected through allylation (Fig chemical yield and enantioselectivity parallely.
4c). As a result, the first two electrostatic processes (i) and (ii) may
N
N
N
N
H
H
O
O
H
O
H
O
O
O
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
OMe
O
O
H
O
4Br-
4Br-
O
OMe
H
O
O
OMe
O
O
O
H
H
H
H
OMe
N
N
N
N
Fig. 3 Detachment/deactivation of CMOC due to no bond resonance formation.
MeO
N
MeO
Spacer
O
N
N
H
Spacer
Spacer
O
O
H
O
O
OH
O
N
O
MeO
O
O
OMe
H
O
OH
O
N
O
N
MeO
H
H
O
N
OMe
N
N
b
a
c
Ion -pair formed between R4N+
of CMOCs with anion of the
nitroolefin and dimethylmalonate
due to electrostatic attraction
Ion -pair formed between R4N+
of CMOCs with anion of the
Hydrogen bonding between enolate anion
of dimethylmalonate, nitro olefin
and free -OH present in C9 position of
CMOCs
nitro olefin due to electrostatic attraction
Fig. 4 Formation of various intermediates/molecular assemblies during enantioselective Michael addition of nitroolefin using C9 free –OH
& allyl protected CMOCs.
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Table 5 Catalytic asymmetric Michael addition reaction of various Michael donors 9 (a-c) to nitrostyrene derivatives 8 (a-e) under
CMOCs conditions.
R1
R1
NO2
CMOCs (7a/7b,
1 mol%)
NO2
*
R1 R1
R
Et3N, EtOH
rt, 30 min
R
9
8
10-12
R = -H, -Cl, -OMe, -CH3, -NO2
R1= -CO2Et, -CO2Me, -CN
Entry
Nitroolefins
R
R1
Catalyst
Producta
Yield %b
% of eec
Abs. conf.d
1
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
8b
8b
8c
8c
8c
8c
8c
8c
8d
8d
8d
8d
8d
8d
8e
8e
8e
-H
-COOEt
-COOEt
-COOMe
-COOMe
-CN
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
10a
10a
11a
11a
12a
12a
10b
10b
11b
11b
12b
12b
10c
10c
11c
11c
12c
12c
10d
10d
11d
11d
12d
12d
10e
10e
11e
96
96
94
94
97
97
93
93
90
90
97
97
92
92
90
90
94
94
92
92
90
90
95
95
85
85
80
99
99
98
98
99
99
95
95
91
92
96
96
95
95
91
91
96
96
90
90
89
89
97
97
95
95
93
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
2
-H
3
-H
4
-H
5
-H
6
-H
-CN
7
-Cl
-COOEt
-COOEt
-COOMe
-COOMe
-CN
8
-Cl
9
-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
-Cl
-Cl
-Cl
-CN
-OMe
-OMe
-OMe
-OMe
-OMe
-OMe
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-NO2
-NO2
-NO2
-COOEt
-COOEt
-COOMe
-COOMe
-CN
-CN
-COOEt
-COOEt
-COOMe
-COOMe
-CN
-CN
-COOEt
-COOEt
-COOMe
28
29
30
8e
8e
8e
-NO2
-NO2
-NO2
-COOMe
-CN
-CN
7b
7a
7b
11e
12e
12e
80
90
90
93
95
95
R
R
R
a The Michael reaction of different Nitroolefins 8 (a-e) (0.067 mmol), various Michael donors 9(a-c) (0.073 mmol), CMOCs 7 (7a/7b, 1 mol%),
with 1 ml Ethanol and triethylamine (0.073 mmol) in room temperature. b Isolated yield of purified material. c Enantiopurity was determined
d
by HPLC analysis of the Michael adduct (10-12 (a-e)) using a chiral column (Chiralcel
configuration was determined by comparison of
OD-H) with hexane-IPA as solvents. Absolute
the
HPLC
retention
time.12b
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5OB01351H
Journal Name
ARTICLE
Preparation of tetraester (3).27
A
stirred mixture of
Conclusion
pentaerythritol tetrabromide (5g, 12.89 mmol), methyl-4-
hydroxybenzoate (7.84g, 51.52 mmol) and K2CO3 (23.15g, 167.49
mmol) in DMF was heated at 1500C and reflux for about 32 h. The
solution was then cooled, water (100 mL) was added, and the
mixture was extracted twice with ethyl acetate. The organic layers
were combined, washed with water and brine, and dried over
Na2SO4. Removal of volatiles under reduced pressure left a residue
that was purified by column chromatography (silica, ethyl acetate
(4%)/hexane (96%), isolated yield of 3 (8.46g, 97%). Colourless solid.
Mp: 199-200 °C. FT-IR = 1710cm-1(C=O stretching), 1H NMR (300
We have designed
a new class of tetrafunctional chiral
organocatalysts by a reasonable combination of readily available
cinchona alkaloid with penta erythritrol based tetrabromide. The
catalysts 7 (7a and 7b) exhibited the best performance in the
asymmetric Michael addition of nitroolefins with various Michael
donors such as dimethylmalonate, diethylmalonate and
malononitrile. The corresponding products can be obtained in
moderate to high yields with excellent enantioselectivities (up to
99%) under mild reaction conditions.
MHz, CDCl3) δH: 7.97 (d, J = 8.9 Hz, 8H), 6.89 (d, J = 8.8 Hz, 8H), 3.87
(s, 12H), 3.84 (s, 8H); 13C NMR (75 MHz, CDCl3) δC: 166.72, 163.04,
Experimental section
131.21, 122.36, 113.27, 55.03, 51.37, 42.11.
Materials and Methods
Preparation of tetra alcohol (4).27 The tetraester 3 (3g, 4.45
mmol) was reduced with LiAlH4 (1g, 26.61 mmol) using THF (40 mL)
as a solvent and the reaction mass was cooled to 0°C for 4 hours.
The reaction mixture was extracted with ethyl acetate. The organic
layers were combined, washed with water and brine, and dried
over Na2SO4. Removal of volatiles under reduced pressure left a
residue that was purified by column chromatography, ethyl
acetate/hexane (20:80), isolated yield of 4 (2.25g, 90%). Colourless
solid: Mp: 135-136 °C. FT-IR= 3255(O-H stretching), 2920cm-1(C-H
All the chemicals and reagents used in this work were of analytical
grade. Allylbromide, (+)-cinchonine, HBr in acetic acid,
benzaldehyde, 4-chlorobenzaldehyde, 4-methylbenzaldehyde,
anisaldehyde, were obtained from Alfa Aesar, pentaerythritol tetra
bromide,4-hydroxy benzoic acid, LiAlH4, 4-nitrobenzaldehyde,
nitromethane, potassium tert-butoxide, cesium carbonate and
potassium carbonate were obtained from Sigma Aldrich, sodium
hyroxide, pottassium hydroxide, were obtained from Merck and all
the solvents were obtained from Laboratory reagent grade.
The melting points were measured in open capillary tubes and are
uncorrected.
stretching), 1H NMR (300 MHz, CDCl3) δH: 7.29 (d,
6.89 (d,
= 8.6 Hz, 8H), 4.61 (s, 8H), 3.81 (s, 8H); 13C NMR (75 MHz,
J = 8.4 Hz, 8H),
J
CDCl3) δC: 158.91, 132.98, 128.46, 113.71, 64.68, 55.10, 41.54.
Preparation of tetra bromide (Scaffold 5).27 HBr in acetic acid
(30 mL) was taken in a pre-dried RB flask and tetra alcohol 4 (2g,
3.56 mmol) was added under nitrogen atmosphere at 0 °C. After
stirring for about 6hrs, the reaction was monitored by TLC, the
reaction mixture was poured on to 10% sodium bicarbonate
solution and extracted with ethyl acetate, washed with brine and
dried over sodium sulphate. Concentrated it and purified by column
chromatography using pet. Ether and ethyl acetate as an eluent
(8:2). Isolated yield of 5 is (2.45g, 85%). Off-white solid, Mp: 169-
The 1H and 13C NMR spectra were recorded on a Bruker
(Avance) 300 and 400 MHz NMR instrument using TMS as an
internal standard and CDCl3 as a solvent. Standard Bruker software
was used throughout. Chemical shifts are given in parts per million
(δ-scale) and the coupling constants are given in Hertz. Silica gel-G
plates (Merck) were used for TLC analysis with a mixture of n-
hexane and ethyl acetate as an eluent. Column chromatography
was carried out in silica gel (60-120 mesh) using n-hexane and ethyl
acetate as an eluent. FT-IR spectroscopy measured in a JASCO
FT/IR-410 spectrometer and KBr used as pellets. Mass spectra were
analysed by Voyager DE PRO Biospectrometry Workstation (Applied
Biosystems) matrix-assisted laser desorption ionization time-of-
flight (MALDI-TOF) mass spectroscopy (MS) instrument. A pulsed
nitrogen laser of 337 nm was used, and the TOF was operated in
the delayed extraction mode. The HPLC were recorded in
SHIMADZU LC-6AD with Chiral Column (Chiral Cel OD-H), using HPLC
grade n-hexane and isopropanol solvent. Optical rotations were
measured on Rudolph Research Analytical AUTOPOL-II (readability
170 °C. 1H NMR (300 MHz, CDCl3) δH: 7.31(d,
= 8.6 Hz, 8H), 4.64 (s, 8H), 3.83 (s, 8H); 13C NMR (75 MHz, CDCl3)
J = 8.5 Hz, 8H), 6.91 (d,
J
δC: 158.91, 132.98, 128.46, 113.71, 55.10, 41.85, 35.09.
Synthesis of cinchonine (contains free C9-OH) based
multifunctional organocatalyst (7a). A mixture of (0.1g, 10 mmol),
tetra bromide 5 and cinchonine free C9ꢀOH 6a (30 mmol) was
dissolved in 5 ml of EtOH:DMF:ACN (30:50:20 ratio) and whole
reaction mixture was refluxed for overnight, the white solid was
filtered off, washed with diethylether and dried it, to get pure white
1
±0.01°) and AUTOPOL-IV (readability ±0.001°) automatic tetraꢀsite containing organocatalyst (7a) (95% yield). H NMR (400
MHz, CDCl3) δH: 8.82 (d, J = 4.5 Hz, 4H), 8.13 (d, J = 8.2 Hz, 4H),
8.04 (d, J = 5.6 Hz, 4H), 7.76 (d, J = 4.5 Hz, 4H), 7.64 (d, J = 4.4
polarimeters.
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ARTICLE
Journal Name
Hz, 4H), 7.58 (m, 8H), 7.14 (m, 4H), 6.65 (d, J = 8.6 Hz, 8H), 6.48
(s, 4H), 5.83 (d, J = 12.0 Hz, 4H), 5.66 (m, 4H), 5.50 (d, J = 12.0
Hz, 4H), 5.41 (m, 4H), 4.93 (m, 4H), 3.77 (s, 16H), 3.17 (m, 8H),
2.78 (m, 8H), 2.38 (m, 4H), 1.86 (m, 16H), 1.46 (m, 4H). ); 13C
NMR (100 MHz, CDCl3) δC: 156.84, 149.40, 149.24, 148.58,
137.13, 129.82, 129.36, 127.68, 125.48, 123.30, 120.38.119.14,
117.22, 114.31, 81.02, 66.42, 63.78, 61.80, 59.17, 52.08, 40.43,
(75 MHz, DMSO-d6) δC 140.10, 138.83, 132.96, 131.10, 130.63,
130.05.
(E)-1-chloro-4-(2-nitrovinyl) benzene (8b). Light yellow colour
solid, yield: 97%, Mp: 113-114 °C. 1H NMR (300 MHz, CDCl3) δH 7.97
(d, J = 13.6 Hz, 1H), 7.62 (d, J = 13.6 Hz, 1H), 7.46 (m, 4H); 13C NMR
(75 MHz, CDCl3) δC 137.51, 137.39, 137.27, 130.39, 129.07, 128.40.
(E)-1-methoxy-4-(2-nitrovinyl) benzene (8c). Yellow colour
solid, yield: 87%, Mp: 85-88 °C. 1H NMR (300 MHz, CDCl3) δH 7.98 (d,
J = 13.5 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.50 (m, 2H), 6.96 (d, J = 8.8
Hz, 2H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δC 163.04, 139.15,
135.13, 131.29, 122.69, 115.10, 55.65.
38.01, 28.80, 26.10, 23.19; MS (MALDIꢀ TOF): m/z calculated for
25
C
109H120Br4N8O8: 1984.5941; found 1984.5459. [α]D
= +0.71
(c=0.14, CHCl3).
Synthesis of allylated cinchonine based multifunctional
organocatalyst (7b). A mixture of (0.1g, 10 mmol), tetra bromide 5
(E)-1-methyl-4-(2-nitrovinyl) benzene (8d). Yellow colour solid,
isolated yield: 96%, Mp: 106-107 °C. 1H NMR (300 MHz, CDCl3) δH
7.99 (d, J = 13.6 Hz, 1H), 7.58 (d, J = 13.6 Hz, 1H), 7.45 (d, J = 7.8 Hz,
2H), 7.23 (d, J = 7.4 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3)
δC 143.23, 139.29, 136.39, 130.25, 129.31, 127.38, 21.79.
and
O
-allylcinchonine26 6b (30 mmol) was dissolved in 5 ml
THF:ACN (1:1 ratio) and heated to reflux for about overnight, the off
white solid was filtered, washed with diethylether and dried it, to
get pure off white tetra-site organocatalyst (7b) (96% yield). 1H
NMR (400 MHz, CDCl3) δH: 8.83 (d,
4H), 8.05 (d, = 5.6 Hz, 4H), 7.77 (d,
Hz, 4H), 7.60 (m, 8H), 7.13 (m, 4H), 6.65 (d,
4H), 5.69 (dd, = 17.2, 9.3 Hz, 4H), 5.28 (dd,
4.92 (d, = 17.1 Hz, 4H), 4.87 (d, = 11.5 Hz, 4H), 3.91 (m, 8H), 3.71
(s, 16H), 3.41 (s, 4H), 3.06 (dd, = 13.6, 12.8 Hz, 8H), 2.64 (m, 4H),
2.25 (s, 4H), 1.79 (s, 4H), 1.52 (d,
= 11.2 Hz, 12H), 0.81 (m, 4H); 13
J
= 4.5 Hz, 4H), 8.14 (d,
= 4.5 Hz, 4H), 7.64 (d,
= 8.6 Hz, 8H), 5.90 (m,
= 17.2, 9.3 Hz, 12H),
J
= 8.2 Hz,
(E)-1-nitro-4-(2-nitrovinyl) benzene (8e). Yellow colour solid,
J
J
J
= 4.4
1
isolated yield: 90%, Mp: 198-200 °C. H NMR (300 MHz, DMSO-d6
)
J
δH 8.30 (d, J = 13.4 Hz, 2H), 8.23 (d, J = 12.2 Hz, 2H), 8.06 (d, J = 8.5
Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δC 149.15, 141.06, 137.00,
136.72, 131.06, 124.32.
J
J
J
J
J
Characterization of Michael adducts (10-12 (a-e))
J
C
(R)-Diethyl 2-(2-nitro-1-phenylethyl) malonate (10a). Colourless
NMR (100 MHz, CDCl3) δC: 156.66, 149.97, 149.49, 148.27, 137.57,
134.59, 129.30, 129.15, 127.14, 125.64, 122.63, 120.43, 118.95,
117.69, 114.47, 78.05, 75.49, 72.24, 65.75, 61.54, 59.56, 52.36,
40.67, 38.43, 28.74, 26.51, 22.79; MS (MALDI- TOF): m/z calculated
solid, yield: 96%, Mp: 59-61 °C, 1H NMR (300 MHz, CDCl3) δH 7.35
(m, 5H), 4.93 (m, 2H), 4.25 (m, 4H), 4.01 (q,
=
J = 7.1 Hz, 1H), 3.82 (d, J
9.3 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δC 168.00, 167.37, 136.92, 129.46, 128.86, 128.59,
78.21 62.64, 62.38, 55.61, 43.57, 14.57, 14.25. The enantiomeric
excess was determined by HPLC, Chiral cel (OD-H), 240 nm, hexane:
25
for C121H136Br4N8O8: 2144.7193; found 2144.7438. [α]D = +0.71
(c=0.14, CHCl3).
IPA 99: 1, flow rate: 1 mL min-1, retention time: 2.23 min (major),
General method for the synthesis of nitroolefins (8a-e).14-15
The nitroolefins 8 obtained by the modified procedure.14 Aromatic
aldehyde (1 mmol), nitromethane (1 mmol) was dissolved in
methanol and the reaction mass was cooled to ꢀ50C. Further NaOH
(1.2 mmol) was added slowly into the reaction mass through
addition funnel. Finally the reaction mixture was stirred for about
1hr, the reaction was monitored by TLC, after completion of the
reaction, the mixture was neutralized by 4N HCl, and after
neutralization the pale yellow colour solid nitroolefin was formed.
General method for the synthesis of enantioselective catalytic
Michael addition of nitroolefins with various Michael donors
under CMOCs conditions (10-12 (a-e)). To a mixture of nitroolefin 8
(aꢀe, 0.1 mmol), Michael donor (diethyl malonate, dimethyl
malonate, malononitrile 9 (aꢀc, 0.12 mmol) and CMOCs (1 mol %) 7
(7a/7b) were dissolved in 1 ml of ethanol and added of triethylamine.
Then the reaction mixture was stirred for 30 min, after that the
reaction mixture was extracted with ethylacetate, washed with water
(3 × 2 ml), then washed with brine (5 ml), dried over sodium
sulphate and concentrated it. The crude material was purified by
column chromatography on silica gel (ethylacetate and nꢀhexane as
an eluent), to afford the corresponding Michael adducts (10ꢀ12 (aꢀ
e)). The enantiomeric excess of Michael adducts were determined by
chiral stationaryꢀphase HPLC analysis.
25.4
16.61 min (minor). [α]D
= +2.85 (c=0.22, CH2Cl2), (99% ee, (R)-
isomer).The absolute stereochemistry of the addition product was
assigned as (R) by comparison of the optical data with literature
28
reported value 29: [α]D
isomer).
= +6.04 (c=1.10, CHCl3), (95% ee, (R)-
(R)-Diethyl 2-(1-(4-chlorophenyl)-2-nitroethyl) malonate (10b).
Pale yellow solid, yield: 93%, Mp: 43-47 °C, 1H NMR (300 MHz,
CDCl3) δH 7.30 (d,
J
= 8.5, 2H), 6.83 (d, ,
J = 8.4 2H), 4.90 (m, 2H),
4.25 (m, 4H), 4.04 (q,
J
= 7.1, 1H), 3.78 (d, J = 9.3 Hz, 1H), 1.27 (t, J =
7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC
167.10, 166.54, 134.46, 134.23, 129.72, 129.42, 77.65, 62.74, 62.52,
54.58, 42.73, 14.17, 14.02. The enantiomeric excess was
determined by HPLC, Chiral cel (OD-H), 245 nm, hexane: IPA 99:1,
flow rate: 1 mL min-1, retention time: 2.33 min (major), 22.37 min
(minor). [α]D 27.2 = +2.19 (
c= 0.32, CH2Cl2), (95% ee, (R)-isomer).
(R)-Diethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl) malonate
(10c). Colourless oil, yield: 92%, 1H NMR (300 MHz, CDCl3) δH
7.15 (d, J = 8.5, 2H), 6.83 (d, J = 8.4, 2H), 4.85 (m, 2H), 4.25 (m,
4H), 4.02 (q, J = 7.1, 1H), 3.79 (d, J= 8.6 Hz, 1H), 3.77 (s, 3H)
(merged), 1.26 (t, J = 7.1, 3H), 1.06 (t, , J = 7.1, 3H); 13C NMR (75
MHz, CDCl3) δC 167.66, 167.01, 159.65, 129.30, 128.31, 114.47,
78.05, 62.18, 61.93, 55.35, 42.51, 14.08, 13.90. The enantiomeric
excess was determined by HPLC, Chiral cel (ODꢀH), 245 nm,
hexane: IPA 99: 1, flow rate: 1 mL minꢀ1, retention time: 2.78 min
27.2
Characterization of nitroolefins (8a-e)
(major), 10.87 min (minor). [α]D
ee, ( )-isomer).
= +2.95 (c=0.17, CH2Cl2), (95%
R
(E)- (2-nitrovinyl) benzene (8a). Light yellow colour solid, yield:
96%, Mp: 57-58 °C.1H NMR (300 MHz, CDCl3) δH 8.02 (d, J = 13.6 Hz,
1H), 7.60 (d, J = 13.7 Hz, 1H), 7.54 (m, 2H), 7.43 (m, 3H); 13C NMR
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5OB01351H
Journal Name
(R)-Diethyl
ARTICLE
2-(2-nitro-1-p-tolylethyl)
malonate
(10d). 1, flow rate: 1 mL min-1, retention time: 2.50 min (major), 12.19 min
Colourless oil, yield: 92%, 1H NMR (300 MHz, CDCl3) δH 7.45 (d,
J
=
(minor). [α] D 25 = +2.29 (
c= 0.07, CHCl3), (89% ee, (R)-isomer).
7.8 Hz, 2H), 7.25 (d, ,
J = 7.4 Hz, 2H), 4.90 (m, 2H), 4.23 (m, 4H),
4.01 (q, = 7.1 Hz, 1H), 3.79 (d, J = 9.3 Hz, 1H), 2.29 (s, 3H), 1.25 (t,
=
J
J
(R)-Dimethyl 2-(2-nitro-1-(4-nitrophenyl) ethyl)malonate (11e).
1
7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC Yellow oil, yield: 80%, H NMR (300 MHz, CDCl3) δH 8.20 (d, J= 8.7
167.60, 166.98, 138.13, 133.21, 129.68, 127.93, 77.88, 62.24, 61.93, Hz, 2H), 7.46 (d, J= 8.7 Hz, 2H), 4.95 (m, 2H), 4.39 (m, 1H), 3.87 (d,
J
55.14, 42.34, 21.12, 14.06, 13.85. The enantiomeric excess was = 8.8 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δC
determined by HPLC, Chiral cel (OD-H), 245 nm, hexane: IPA 99: 1, 167.42, 166.89, 147.99, 143.68, 129.26, 124.32, 77.58, 54.25, 53.44,
flow rate: 1 mL min-1, retention time: 2.07 min (major), 20.75 min 53.29, 42.63. The enantiomeric excess was determined by HPLC,
(minor). [α]D 25 = +2.86 (
c
= 0.35, CH2Cl2), (90% ee, (
R)-isomer).
Chiral cel (OD-H), 240 nm, hexane: IPA 99: 1, flow rate: 1 mL min-1,
retention time: 2.07 min (major), 20.74 min (minor). [α] D 25 = +2.32
R)-Diethyl 2-(2-nitro-1-(4-nitrophenyl) ethyl) malonate (10e).
Yellow colour oil, yield: 85%, 1H NMR (300 MHz, CDCl3) δH 8.20 (d,
= 8.7 Hz, 2H), 7.45 (d, , = 8.5Hz, 2H), 4.95 (m, 2H), 4.33 (m, 4H),
4.06 (q,
(
c
= 0.45, CHCl3), (93% ee, (
R)-isomer).
J
J
(R)-2-(2-nitro-1-phenylethyl) malononitrile (12a). White solid,
J
= 7.1 Hz, 1H), 3.82 (d, J = 9.0 Hz, 1H), 1.27 (t, J = 7.0 Hz, yield: 97%, Mp: 55-56 °C, 1H NMR (300 MHz, CDCl3) δH 7.56 (m, 3H),
3H), 1.10 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC 166.87, 7.45 (m, 2H), 4.91 (m, 2H), 4.50 (d, J= 6.6 Hz, 1H), 4.22 (m, 1H); 13C
166.31, 147.78, 143.67, 129.22, 124.08, 77.42, 62.51, 62.30, 55.36, NMR (75 MHz, CDCl3) δC 131.86, 130.09, 129.30, 127.76, 110.51,
42.50, 13.94, 13.79. The enantiomeric excess was determined by 110.21, 77.97, 42.68, 29.23. The enantiomeric excess was
HPLC, Chiral cel (OD-H), 245 nm, hexane: IPA 99: 1, flow rate: 1 mL determined by HPLC, Chiral cel (OD-H), 240 nm, hexane: IPA 99: 1,
25
min-1, retention time: 2.33 min (major), 22.37 min (minor). [α] D
=
flow rate: 1 mL min-1, retention time: 2.15 min (major), 15.34 min
(minor). [α]D = +2.78 (c =0.18, CH2Cl2), (99% ee, (R)-isomer). The
25
+2.12 (
c
=0.33, CH2Cl2), (95% ee, (R)-isomer).
absolute stereochemistry of the addition product was assigned as
) by comparison of the optical data with literature reported value
solid, yield: 94%, Mp: 64-65 °C, 1H NMR (300 MHz, CDCl3) δH 7.30 29 [α]D 24.1 = +5.4 (c= 0.5, CHCl3).
(m, 3H), 7.25 (m, 2H), 4.90 (m, 2H), 4.23 (m, 1H), 3.86 (d, = 6.9 Hz,
(R)-Dimethyl 2-(2-nitro-1-phenylethyl) malonate (11a). White
(R
J
(R)-2-(1-(4-chlorophenyl)-2-nitroethyl) malononitrile (12b).
1
1H), 3.73 (s, 3H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δC 167.85, White solid, yield: 97%, Mp: 88-90 °C, H NMR (300 MHz, CDCl3) δH
167.25, 136.19, 128.97, 128.37, 127.89, 76.84, 54.71, 52.96, 7.43 (d, J= 8.5 Hz 2H), 7.36 (d, J= 8.9 Hz, 2H), 4.95 (m, 2H), 4.40 (d,
52.75,42.95. The enantiomeric excess was determined by HPLC, J= 8.6 Hz, 1H), 4.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δC 135.70,
Chiral cel (OD-H), 240 nm, hexane: IPA 99: 1, flow rate: 1 mL min-1, 129.30, 128.75, 128.31, 110.77, 110.59, 78.05, 42.39, 27.06. The
27
retention time: 2.09 min (major), 26.89 min (minor). [α] D = +2.73 enantiomeric excess was determined by HPLC, Chiral cel (OD-H),
(
c
=0.95, CHCl3), (98% ee, (
of the addition product was assigned as (
optical data with literature reported value
=1.02, CHCl3), (93% ee, ( )-isomer).
R
)-isomer). The absolute stereochemistry 245 nm, hexane: IPA 99: 1, flow rate: 1 mL min-1, retention time:
R
) by comparison of the 2.12 min (major), 11.31 min (minor). [α]D 25 = +3.16 (c=0.19, CH2Cl2),
29
25
:
[α]
= +4.40 (96% ee, (
product was assigned as (
literature reported value 29: [α]D 24.4 = +7.2 (c =0.5, CHCl3), (76% ee,
R
)-isomer). The absolute stereochemistry of the addition
D
(c
S
R) by comparison of the optical data with
(R)-Dimethyl
2-(1-(4-chlorophenyl)-2-nitroethyl)malonate
(
R
)-isomer).
(11b). White solid, yield: 90%, Mp: 80-81 °C, 1H NMR (300 MHz,
CDCl3) δH 7.29 (d, J= 8.2 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 4.93 (m, 2H),
(R)-2-(1-(4-methoxyphenyl)-2-nitroethyl) malononitrile (12c).
1
4.23 (m, 1H), 3.87 (d,
J
= 6.9 Hz, 1H), 3.74 (s, 3H), 3.53 (s, 3H); 13C White solid, yield: 94%, Mp: 82-94 °C, H NMR (300 MHz, CDCl3) δH
NMR (75 MHz, CDCl3) δC 167.26, 166.67, 134.37, 134.22, 129.04, 7.13 (d, J= 8.7 Hz, 2H), 6.82 (d, J= 8.7 Hz, 2H), 4.90 (m, 2H), 4.41 (d,
128.98, 76.51, 54.03, 53.22, 53.07, 42.41. The enantiomeric excess J= 5.7 Hz, 1H) 4.06 (m, 1H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δC
was determined by HPLC, Chiral cel (OD-H), 245 nm, hexane: IPA 99: 160.93, 129.21, 123.33, 115.47, 110.55, 110.28, 76.75, 55.37, 43.12,
1, flow rate: 1 mL min-1, retention time: 2.68 min (major), 23.23 min 27.61. The enantiomeric excess was determined by HPLC, Chiral cel
(minor). [α] D 25 = +2.41 (
c
=0.75, CHCl3), (92% ee, (
(R)-Dimethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl)malonate time: 2.12 min (major), 11.31 min (minor). [α]D 25.2 = +3.74 (c =0.33,
(11c). Yellow oil, yield: 90%, 1H NMR (300 MHz, CDCl3) δH 7.12 (d, J= CH2Cl2), (96% ee, (
)-isomer). The absolute stereochemistry of the
8.7 Hz, 2H), 6.82 (d, J= 8.7 Hz, 2H), 4.90 (m, 2H), 4.19 (m, 1H), 3.82 addition product was assigned as ( ) by comparison of the optical
(d,
= 9.2 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.53 (s, 3H); 13C NMR data with literature reported value 29: [α]D 27.2 = +7.1 (c = 1.0, CHCl3),
R
)-isomer).
(OD-H), 245 nm, hexane: IPA 99: 1, flow rate: 1 mL min-1, retention
R
R
J
(75 MHz, CDCl3) δC 168.00, 167.40, 159.54, 129.11, 127.97, 114.46, (78% ee, (
R)-isomer).
77.75, 55.29, 54.95, 53.08, 52.91, 42.40. The enantiomeric excess
was determined by HPLC, Chiral cel (OD-H), 245 nm, hexane: IPA 99:
(R)-2-(2-nitro-1-p-tolylethyl) malononitrile (12d). White solid,
1, flow rate: 1 mL min-1, retention time: 2.50 min (major), 12.19 min yield: 95%, Mp: 99-100 °C, 1H NMR (300 MHz, CDCl3) δH 7.29 (m,
(minor). [α] D 25 = +1.38 (
c
=0.94, CHCl3), (91% ee, (
R
)-isomer).
4H), 4.91 (m, 2H), 4.28 (d, J= 6.0 Hz, 1H), 4.05 (m, 1H), 2.37 (s, 3H);
13C NMR (75 MHz, CDCl3) δC 139.31, 130.09, 128.34, 127.23, 109.80,
(11d). 109.61, 76.74, 42.38, 27.23, 21.79. The enantiomeric excess was
(R)-Dimethyl
2-(2-nitro-1-p-tolylethyl)malonate
Colourless oil, yield: 90%, 1H NMR (300 MHz, CDCl3) δH 7.63 (d, J= determined by HPLC, Chiral cel (OD-H), 245 nm, hexane: IPA 99: 1,
13.6 Hz, 2H), 7.45 (d, J= 7.8 Hz, 2H), 4.91 (m, 2H), 4.23 (m, 1H), 3.87 flow rate: 1 mL min-1, retention time: 2.12 min (major), 15.93 min
(d,
J
= 6.9 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 3H), 2.42 (s, 3H); 13C NMR (minor). [α]D 29 = +2.73 (
c
= 0.22, CH2Cl2), (97% ee, (
R)-isomer).
(75 MHz, CDCl3) δC 167.81, 167.20, 138.25, 133.19, 129.05, 127.77,
77.55, 54.94, 52.89, 52.72, 42.20, 21.41. The enantiomeric excess
(R)-2-(2-nitro-1-(4-nitrophenyl) ethyl) malononitrile (12e).
was determined by HPLC, Chiral cel (OD-H), 240 nm, hexane: IPA 99: Yellow solid, yield: 90%, Mp: 141-143 °C, 1H NMR (300 MHz, CDCl3)
δH 8.20 (d, J= 8.7Hz, 2H), 7.46 (d, J= 8.5 Hz, 2H), 5.21 (d, J= 6.9 Hz,
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1H), 4.55 (d, J= 7.4 Hz, 1H), 3.62 (m, 2H); 13C NMR (75 MHz, CDCl3) 10 (a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc., 2003,
δC 149.62, 142.62, 130.68, 125.50, 112.50, 112.20, 78.05, 42.34,
27.46. The enantiomeric excess was determined by HPLC, Chiral cel
(OD-H), 245 nm, hexane: IPA 99: 1, flow rate: 1 mL min-1, retention
time: 2.33 min (major), 22.37 min (minor). [α]D = +1.54 (c = 0.13,
CH2Cl2), (95% ee, (R)-isomer).
125, 12672-12673; (b) T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J.
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Acknowledgment
We acknowledge the financial support of the Department of
Science and Technology, New Delhi, India (Grant No.
SR/F/1584/2012-13), University Grants Commission, New Delhi,
India (Grant No. UGC No.41-215/2012 (SR) and Council of Scientific
and Industrial Research, New Delhi, India (Grant No.
01(2540)/11/EMR-II).
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