Abstract
The thesis entitled “Synthesis of mixed β-peptides, Imidazoles and Base Catalysed
Condensation Reactions” is divided into two chapters. First chapter is dealt with the
synthesis of (R) and (S)--homoserine, oxetane -amino acid, enatiomeric C-linked
carbo--amino acids from D-and L-arabinose and their use in the synthesis of peptides.
Second chapter describes the synthesis of imidazoles and Knovenagel condensations.
Chapter I: Synthesis of new β-amino acids and mixed β-peptides
This chapter is dealt with synthesis of (S)- and (R)--hSer (from L- and D-phenyl
alanine), oxetane-β-amino acid and new enantiomeric C-linked carbo-β-amino acids
and their use in the design and synthesis of mixed carbo-β-peptides.
Glycolipids and glycoproteins play a major role in inflammation, immune
response, metastasis, fertilization and many other biomedically important processes.1-4
Majority of the natural proteins contain (oligo)-saccharide side chains and the saccharide
residues are covalently linked to the protein backbone either N- (via asparagines) or Oglycosidically (via serine, threonine, or tyrosine).5 The incorporation of C-glycosyl amino
acids in glycopeptides may serve in preparing chemically and metabolically resistant
analogues that display inhibitor activity towards O- or N-glycosidases.6 β-Amino acids
are part structures of several natural products and very important components. Due to the
importance of such unusual amino acids and their nonavailability from ‘chiral pool’ work
was undertaken towards their synthesis and development of non-natural peptides with
new conformations.
Seebach et al.7a and Gellman et al.7b designed β-peptides with 14- and 12-helical
structures by using aliphatic and constrained cyclic β-amino acids8 respectively. Even
though sugar amino acids have been used for the peptide synthesis, synthesis of βpeptides having carbohydrates as side chains is not reported. For the synthesis of such
peptides using C-linked carbo-β- and -amino acids (/-Caa), with carbohydrate side
chains, TBAF9 was used an efficient base in promoting the aza-Michael addition of
benzylamine on sugar-based γ-alkoxy α,β-unsaturated ester10 A to result in B (Scheme 1).
The continued interest in developing new bases for efficient aza-Michael addition of
1
Abstract
amine an α,β-unsaturated ester, revealed DBU as an efficient base to give B while
reaction of A with BnNH2 gave B and C.
Scheme 1
O
O
H3CO
D-Glucose
H3CO
A
TBAF or DBU
BnNH2
O
O
H3CO
68%
O
O
NHBn
O
H3CO
C
O
H3CO
+
O
NHBn
O
H3CO
B
Our earlier work on the carbo-β-peptides,11 prepared from (S)- and (R)- β-Caas
alternatingly resulted in 10/12- and 12/10-mixed helices, wherein conformational
constraints were observed with (S)-β-Caa. Based on the above observation, synthesis of a
new set of monomers such as homoserines (S)-1 and (R)-2 (Figure 1) and small ring
oxetane β-amino acids 3 were envisaged to relieve the constraints. It was assumed that,
such side chains in the new -amino acids would help in the formation of well-defined
helices in the thus made peptides. Similarly, enantiomeric -Caas 4 and 5 (Figure 1) also
were prepared to study the synthesis with alternating chirality.
Figure 1
O
H3CO
NHBo c
OAC
O
O
NHBo c
H3CO
OAC
H3CO
O
NHBo c
O
H3CO
H3CO
O
SOaa (3)
(R)--hSer (2)
(S)--hSer (1)
NHBo c
O
O
H3CO
O
NHBo C
O O
O
H3CO
(R)-Caa (4)
(S)-Caa (5)
Synthesis of β-amino acids 1, 2 and 3
The requisite -amino acids 1 and 2 were prepared from commercially available
L- and D-phenyl alanine respectively. Accordingly, L-phenyl alanine 6 (Scheme 2) was
treated with I2 and NaBH4 in dry THF to afford phenyl alaninol 7, which on reaction with
(Boc)2O in THF gave 8. Acetylation of 8 with Ac2O and oxidative cleavage of phenyl
ring in 9 afforded (S)-β-homoserine 1.
2
O
O
Abstract
Scheme 2
NH2
NH2
a
Ph
7
d
OAc
Ph
8
NHBoc
O
NHBoc
c
OH
Ph
OH
Ph
COOH
6
NHBoc
b
OAc
HO
1
9

a) NaBH4, I2, THF, 18 h, 0 C-reflux; b) (Boc)2O, Et3N, THF, 4 h, rt; c) Ac2O, Et3N, CH2Cl2,
DMAP, 30 min, rt; d) RuCl3, NaIO4, CCl4: CH3CN : H2O, 48 h, rt
Similar sequence of reactions on D-phenyl alanine 10 (Scheme 2) gave (R)-βhomoserine 2.
Scheme 3
NH2
NHBoc
NH2
a
Ph
11
O
NHBoc
c
OAc
Ph
OH
Ph
OH
Ph
COOH
10
b
12
NHBoc
d
OAc
HO
13
2
a) NaBH4, I2, THF, 18 h, 0 oC-reflux; b) (Boc)2O, Et3N, THF, 4 h, rt; c) Ac2O, Et3N, CH2Cl2,
DMAP, 30 min, rt; d) RuCl3, NaIO4, CCl4: CH3CN : H2O, 48 h, rt
The oxetane--amino acid (3, -Oaa) was prepared from D-manitol. Accordingly,
mannitol diacetonide, prepared from D-mannitol, on oxidative cleavage gave (R)glyceraldehye 14 (Scheme 4). Reaction of 14 with allyl bromide and zinc dust12 in THF
at room temperature for 4 h afforded homoallylic alcohol 15, which on osmylation with
catalytic amount of OsO4 and NMO in acetone:water (4:1) at room temperature for 24 h
afforded 16. Further, cleavage of 1,2-diol 16 using NaIO4 in CH2Cl2 and catalytic sat.
NaHCO3 at 0 °C to room temperature for 5 h afforded aldehyde 17, which was used as
such for the next reaction. Aldehyde 17 was treated with NaBH4 in MeOH at 0 °C for 30
min to furnish alcohol 18. Primary alcohol 18 on tosylation with p-TsCl and Et3N in
CH2Cl2 and catalytic amount of DMAP at room temperature for 12 h afforded 19, which
was reacted with NaH in DMF at room temperature for 12 h to give 20 in. Acetonide
deprotection in compound 20, on reaction with 60% aq. AcOH at room temperature for
12 h afforded the diol 21.
3
Abstract
Scheme 4
O
a
O
O
O
CHO
14
O
15
O
OH
OH
e
b
O
O
16
OH
O
c
O
f
17
O
g
O
d
OH
21
O
j
i
H3CO
h
O
20
OH
CHO
OH
HO
O
O
OHC
O
O
OH
OH OH
OTs
19
18
O
NHBn
O
k,l
3
24
H3CO O
23
22
a) Allyl bromide, Zn, THF, sat. NH4Cl, 4 h, rt; b) OsO4, NMO, 4:1, Acetone: water, 24 h, rt;
c) NaIO4, CH2Cl2, sat. NaHCO3, 5 h, rt; d) NaBH4, MeOH, 30 min, 0 oC; e) p-TsCl, Et3N,
DMAP, CH2Cl2, 12 h, rt; f) NaH, DMF, 12 h, rt; g) 60% aq. Acetic acid, 12 h, rt; h) NaIO4,
MeOH-H2O, 1 h, rt; i) Ph3P=CHCO2Me, MeOH, 2 h, rt; j) BnNH2, 12 h, rt; k) 10% Pd/C,
H2, MeOH, 12 h, rt; l) (Boc)2O, Et3N, THF, 4 h, rt
Further, cleavage of 1,2-diol in 21 using NaIO4 in MeOH-H2O at room
temperature for 1 h gave aldehyde 22, which was immediately treated with
(methoxycarbonylmethylene)triphenyl phosphorane in MeOH at room temperature for 2
h to give 23. Reaction of Michael acceptor 23 with benzyl amine (2.5 equivalents)13 at
room temperature gave oxetane-β-amino acid ester 24. Ester 24 was subjected to
hydrogenation with 10% Pd-C in methanol under hydrogen atmosphere and the amine
was treated with (Boc)2O and Et3N in THF to result in 3.
In our reported studies on the carbo--peptides, the epimeric -Caas were utilized
with ‘alternating chirality’. It was planned to synthesise enantiomeric -Caas and use
them in the peptide design with alternating chirality. In this direction, enantiomeric Caas were prepared from D-and L-arabinose. Accordingly, the new C-linked carbo-βamino acid 4 was prepared from L-arabinose as shown in Scheme 5. Readily available L(+)-arabinose was selectively silylated using TBDPSCl in DMF at 0 C to room
temperature for 18 h to afford 25, which was treated with dry acetone, CuSO4 and
catalytic amount of conc. H2SO4 at room temperature for 5 h to furnish 26. Compound 26
was subjected to alkylation using MeI and NaH in THF at 0 °C to room temperature for
12 h to give 27, which on desilylation using TBAF at 0 °C to room temperature for 14 h
4
Abstract
gave 28. Oxidation of 28 with IBX in DMSO gave aldehyde 29, which on Witting
reaction in C6H6 at reflux for 5 h gave 30. Reaction of 30 with benzyl amine (2.5
equivalents) at room temperature for instance gave a separable mixture of C-linked
carbo-β-amino acid esters 31 and 32. Ester 31 was subjected to hydrogenolysis with 10%
Pd-C in methanol under hydrogen atmosphere to give the amine, which on treatment with
(Boc)2O and Et3N in CH2Cl2 afforded 4.
Scheme 5
O
O
d
OR TBDPSO
c TBDPSO
O
TBDPSO
O
a
b
L-(+)-Arabinose
O
MeO
O
HO
HO
OH
27
26
25 R = H
25a R = TBDPS
O
O
O
O
g
O
HO
O
f
e
H3CO
O
H
O
O
O
H3CO
H3CO
28
30
H3CO 29 O
O
NHBn
O
O
NHBn
O
H3CO
O
+
h, i
O
4
H
CO
3
H3CO 31 O
O
H3CO
32
a) TBDPSCl, Imidazole, DMF, 18 h, 0 oC-rt ; b) Acetone, H+, CuSO4, 5 h, rt, ; c) NaH, MeI, THF, 12
h, 0 0C-rt ; d) TBAF, CH2Cl2, 14 h, 0 oC-rt ; e) IBX, DMSO, 6 h, rt; f) Ph3P=CHCO2Me, C6H6, 5 h,
reflux; g) BnNH2, 12 h, rt; h) Pd/C, H2, MeOH, 12 h, rt ; i) (Boc)2O, Et3N, CH2Cl2, 4 h, rt
O
In a similar way, as described for 4, readily available D-(+)-arabinose
was
selectively silylated using TBDPSCl in DMF to afford 33 (Scheme 6). Compound 33 was
treated with dry acetone, CuSO4 and H2SO4 (cat) to furnish 34, which was subjected to
alkylation with MeI and NaH in THF to give 35. Deprotection of 35 using TBAF gave
36, which on oxidation with IBX in DMSO gave aldehyde 37; Witting olefination on 37
in C6H6 at reflux temperature for 5 h gave 38. Reaction of 38 with benzyl amine gave a
separable mixture of Caas 39 and 40. Compound 39 was subjected hydrogenation with
10% Pd/C and resultant amine was treated with (Boc)2O and Et3N in CH2Cl2 to result in
5.
5
Abstract
Scheme 6
O
a TBDPSO
D-(+)-Arabinose
O O
O
H3CO
O
H3CO
b
H3CO
36
NHBnO O
O
O
+
H3CO
H3CO 40
OO
O
TBDPSO
H3CO
34
O O
O
H CO
Ff 3
35
g
H3CO
38
37
NHBn
O O
O
H3CO
c
O
O O
O
H
e
OO
O
TBDPSO
HO
HO
OH
33 R = H
33a R = TBDPS O
HO
d
OR
h, i
5
39
a) TBDPSCl, imidazole, DMF, 18 h, 0 C-rt ; b) Acetone, H+, CuSO4, 5 h, rt, ; c) NaH, MeI, THF, 12
h, 0 C-rt ; d) TBAF, CH2Cl2, 14 h, 0 C-rt ; e) IBX, DMSO, 6 h, 0 C - rt; f) Ph3P=CHCO2Me,
C6H6, 5 h, reflux; g) BnNH2, 12 h, rt; h) Pd/C, H2, MeOH, 12 h, rt ; i) (Boc)2O, Et3N, CH2Cl2, 4 h, rt
Synthesis of mixed β-peptides with epimeric -Caas and (R)/(S)--hSer/(S)--Oaa
Having successfully prepared new -amino acids 1-5, it was firstly proposed to
synthesise mixed -peptides using 41 and 41a alternatingly with 1 and 2 (Figure 2). The
main intention of the work was to understand the impact of a small side chain on the
helix forming capability. Peptides were prepared by using standard peptide coupling
conditions15 in the presence of water soluble 1-hydroxy-1H-benzotriazole (HOBt), 1-[3(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and DIPEA as a
base in dry CH2Cl2.
Figure 2
O
H3CO
NHBoc
O
C
C
O
C4
C1
C3
H3CO
O
H3CO
C
HO
C
C4
C1
O
C3
C2
O
H3CO
(R)--Caa (41)
O
NHBoc
O
C2
O
(S)--Caa (41 a)
NHBoc
O
OAc
HO
(S)--hSer (1)
NHBoc
OAc
(R)--hSer (2)
6
Abstract
In the synthesis of mixed C-linked carbo-β-peptides di-, tri-, tetra- and
pentapeptides 42-45 respectively were prepared with (S)-C-linked carbo-β-amino acid, 41a
and (S)-β-hSer 1, alternatingly by adopting segment condensation method (Scheme 7).
Dipeptide 42 was prepared by condensation of two monomers, (S)-Caa 41a and
(S)--hSer 1. Tripeptide 43 was prepared by coupling of dipeptide amine and acid of (S)-βCaa, while tetrapeptide 44 was prepared by coupling of tripeptide amine and (S)--hSer
acid. The pentapeptide 45 was prepared from tetrapeptide amine 44 and (S)-β-Caa acid.
Scheme 7
H
N
O
H
N
S
H
N S
O
S
OCH3
O
O
O
42
O
OAc
H3CO
H
N
O
O
H3CO
O
O
O
H
N
H
N
O
OAc
H3CO
S
H
N S
O
O
O
H3CO
O
O
H
N
S
O
O
44
O
O
O
43
O
S
O
OAc
H3CO
O
O
H
N
S
H
N S
O
H
N S
O
OCH3
O
H
N
O
O
O
O
O
O
OAc
H3CO
O
O
O
OCH3
O
O
O
O
OAc
H3CO
S
O
OAc
H3CO
H
N S
H
N S
S
OCH3
O
O
O
45
In a further study, it was proposed to use the β-Caa monomer and β-h-Ser with
alternating chirality for the synthesis of new β-peptides. Accordingly, the dipeptide 46,
tripeptide 47, tetrapeptide 48 and pentapeptide 49 (Scheme 8) were prepared from (S)-Clinked carbo-β3-amino acid (Caa) 41a and (R)--h-Ser 2 by using standard peptide coupling
conditions. NMR, CD and MD studies clearly indicated that mixed-β-peptides 48 and 49
folded into 12/10/12- and 10/12/10/12-mixed helical pattern (Figure 3).
7
Abstract
Scheme 8
H
N
O
H
N
R
O
S
O
OAc
H3CO
46
OCH3
O
H
N R
O
O
O
H
N S
O
O
O
H3CO
O
O
AcO
H
N S
O
O
H3CO
47
O
OCH3
O
O
O
12
10
H
N R
O
OAcO
H
N S
O
H3CO
H
N R
O
O
OAcO
48
O
H
N S
O
H3CO
OCH3
O
O
O
O
12
10
10
H
N
O
O
H3CO
O
O
O
O
AcO
H
N
H
N
H
N
O
H3CO
O
O
O AcO
H
N
O
H3CO
O
O
OCH3
O
O
O
49
Figure 3: a) Circular dichroism spectrum of tetrapeptide 48 in CH3OH at concentration of 0.1
mM; b) MD structure (side view) of 48 (bundle of 20 conformers lowest in energy determined by
restrained molecular dynamics).
In a further study, (R)--Caa 41 and (S)--hSer 1 were successfully utilized for
the synthesis of new β-peptides. Accordingly, the dipeptide 50, tripeptide 51, tetrapeptide
52, and pentapeptide 53 (Scheme 9) were prepared. NMR, CD and MD studies clearly
indicated that, these mixed-β-peptides folded in a 12/10- mixed helical pattern. Peptides
51 and 53 have shown 12/10- and 12/10/12/10- mixed helices, while 52 indicated the
presence of a 10/12/10-mixed helix.
8
Abstract
12
Scheme 9
H
N
O
H
N
S
O
R
O
OAc
H3CO
H3CO
O
O
H
N S
O
AcO
R
H
N R
H
N S
O
O
O
H3CO
O
H3CO
O
O
H
N
O
OAc
H3CO
O
R
OCH3
O
O
O
10
AcO
H
N R
OCH3
O
O
H3CO
52
O
O
O
O
12
12
H
N
51
O
H
N
12
O
O
O
O
10
O
H
N S
O
O
O
O
50
H
N R
O
OCH3
10
10
H
N R
S
O
AcO
10
H
N S
O
H3CO
O
O
O
O
AcO
H
N R
O
O
H3CO
O
O
OCH3
O
O
53
Figure 4: CD spectrum of 52 in CH3OH at concentration of 0.1 mM NMR solution structure; (b)
MD structure side view of 52 (bundle of 20 conformers lowest in energy determined by
restrained molecular dynamics).
Similarly, di-, tri- and tetrapeptides 54-56 (Scheme 10) were prepared from (R)Caa 41 and (R)--hSer 2. In
1
H NMR spectra of peptides 46-48, characteristic
information on well-defined secondary structures was not observed. These peptides have
not shown the presence of any secondary structure.
9
Abstract
Scheme 10
H
N
O
H
N
R
O
R
O
OAc
H3CO
H
N
R
O
H3CO
O
O
55
O
H
N
R
O
O
O
O
O
H
N
O
OCH3
O
OAc
H3CO
O
R
OCH3
O
O
O
54
H
N
O
H
N
R
O
H
N
R
O
OAc
H3CO
O
R
O
OAc
H3CO
O
O
O
H
N
R
O
56
OCH3
O
O
O
Thus study on the synthesis of mixed -peptides using (R/S)--Caa and β-hSer
(R/S) amply indicated that the peptides with a CH2OAc side chain also behaved like the
earlier carbo--peptides prepared from alternatingl (R)- and (S)--Caas. Like the
homooligomeric peptides derived from (R)-β-Caa and (S)-β-Caa, the mixed peptides
derived from (R)-β-Caa/(R)--hSer and (S)-β-Caa/(S)--hSer do not present any
secondary structures.
In a further new design, it was planned to synthesize the mixed β-peptides using
the (R)-β-Caa 41 and (S)--Oaa 3 alternatingly. Accordingly, 41 and 3 were successfully
utilized for the synthesis of new mixed-β-peptide 57 (Scheme 11).
Scheme 11
H
N
O
H
N
O
OCH3
O
H3CO
O
O
O
O
O
57
Similarly, dipeptide 58 was prepared from 41 and 3, having 3 at N-terminus
(Scheme 11).
10
Abstract
Scheme 12
H
N
O
H
N
O
O
O
OCH3
O
O
H3CO
O
O
58
However, attempted conversion of the above dipeptides 57 and 58 into the
corresponding higher homologues gave unexpected problems in the synthesis. Hence,
work could not be extended in this direction.
Thus, even though new -Caas were prepared with a CH2OAc and oxetane side
chains and peptides were made, only the peptides with alternating -Caa and β-hSer have
shown well-defined 12/10-mixed helical patterns. However, for reasons not known
enantiomeric -Caas derived from L-and D-arabinose did present difficulties in their
synthesis of enantiomeric β-peptides.
Chapter II described ZrCl4 catalysed synthesis of tri- and tetrasubstituted imidazoles and
Knoevenagel condensation reactions by modified Ni-Al layered double hydroxides
Section A: ZrCl4 Catalysed synthesis of tri- and tetrasubstituted imidazoles
A general protocol has been developed for the rapid synthesis of 2,4,5trisubstituted and 1,2,4,5-tetra-substituted imidazoles in good yields using ZrCl4 as a
catalyst at room temperature (Scheme 13).
The synthetic strategy is based on the condensation of 1,2-diarylethanedienones
with aldehydes or aldehydes and amines resulting in 2,4,5-tri-substituted and 1,2,4,5tetra-substituted imidazoles respectively using 20 mol% of ZrCl4 as a catalyst. Of the
several methods reported in the literature for the synthesis of imidazoles, the four
component one-pot condensation of aryl glyoxals, aldehydes, amines and ammonium
11
Abstract
acetate in refluxing acetic acid is the most desirable and convenient method (Scheme 13).
Scheme 13
Ph
Ph
R-CHO
O
+
NH4OAc, ZrCl4
N
CH3CN, rt
or
Ph
O
R1NH2, NH4OAc,
ZrCl4, CH3CN, rt
Ph
R
N
R1
R = Aliphatic, Aromatic, sugars
R1= Differnt amines
Initially, benzaldehyde (Table 1) with an equimolar quantity of benzil and excess
of ammonium acetate in acetonitrile was treated with 20 mol% ZrCl4 and stirred at room
temperature for 0.75 h to furnish 2,4,5-triphenyl imidazole. The reaction of benzil with a
range of other aromatic aldehydes carrying electron withdrawing or electron releasing
substitutes afforded high yields of products (Table 1). Noteworthy to mention that
reaction of benzil with p-anisaldehyde and excess of ammonium acetate, the reaction was
only 50% complete. Aliphatic aldehydes (entry 6, 7), heterocyclic aldehyde (entry 8a)
and sugar aldehydes (9, 10, 11, 12) too gave the products in high yields. Similarly,
terenaldehyde (entry 13) with two equivalents of benzil and excess of ammonium acetate
gave bis imidazolyl benzene.
This approach was used for the preparation of tetrasubstituted imidazoles too
successfully in good yields. Thus, benzil on reaction with equimolar quantity of
aldehyde, amines (14-16) along with excess of ammonium acetate in acetonitrile at room
temperature furnished 1,2,4,5-tetrasubstituted imidazoles. The reaction was carried out
with aliphatic amine (entry 14), aromatic amine (entry 15) and heterocyclic amine (entry
16) successfully to give 14a, 15a and 16a respectively.
12
Abstract
Table 1: ZrCl4 catalysed synthesis of tri/tetrasubstituted imidazoles
Starting
material
Entry
Time
(h)
Product
Ph
OHC
Yield
(%)
N
1
N
H
Ph
R
R
2
1
1a R = H
0.75
95
2
2a R = Cl
10
93
96
89
3
3
3a R = F
5
4
4
4a R = NO2
7
5
OHC
Ph
O
N
Ph
OHC
O
N
H
Ph
5
N
6
7
CH 3
OHC
CH3
CH 3
7
8
N
H 6a
Ph
6
Ph
CH3
N
N
H
Ph
Ph
6
95
2
91
4
84
5a
CH3
CH3
7a
N
OHC
N
H
Ph
4.5
84
6
84
1.25
88
1.5
87
8a
8
9
9
O
OHC
O
10
13
O
9a
N
OCH3
Ph
O
O
O
O
11a
O
OO
N
H
O
NH2
14
Ph-CHO
H
N
N
13a
15
+
15
NH2
16
N
16
Ph
2
87
Ph
N
Ph
N
14a
CH3-(CH2)5-NH2
Ph-CHO
Ph
85
O
OO
O
CHO
1.5
O
12a
12
O
+
O
N
Ph
Ph
OCH3
N
H
13
14
O
10a
N
Ph
O
N
H
O
O
Ph
Ph
Ph
O
O
O
OO
O
O
N
N
H
H3CO
Ph
11
OHC
N
H
Ph
Ph
10
O
OHC
O
12
N
Ph
O
H3CO
11
Ph
CHO
OHC
Ph
1
86
0.75
88
1.25
89
Ph
N
Ph
N
Ph
N
Ph
15a
Ph
Ph N
+ Ph-CHO
N
16a
13
Abstract
Section B: Knovenagel condensation by modified Ni-Al layered double hydroxides.
Calcined Ni-Al hydrotalcite is an efficient and environmentally attractive solid
base catalyst for the selective synthesis of -nitroalkanols, ,- unsaturated nitriles or
esters by Henry or Knoevenagel reactions of the activated nitro alkanes, carboxylic esters
or nitriles with various aldehydes respectively (Scheme 14). The main advantages with
this catalytic system are simple work-up procedure and reusability with quantitative
yields.
Scheme 14
R
O
H
R1
CN
Calcined Ni-Al HT
R
CN
room temperature
H
R1
A
R = Aryl, R1 = CN / CO2Et
As is seen from Table 2, all the aldehydes 1-8 underwent smooth condensation
selectively to give dehydrated products 1a-8a, 1b-4b, 6b-8b without any self-condensed
or hydrated products of Knoevenagel adducts. The reaction using calcined Ni-Al
hydrotalcite catalyst between benzaldehyde (1) and ethyl cyanoacetate (entry 1, Table 2)
gave selectively Knoevenagel adduct 1b whereas alkali metal containing MCM-41 gives
a mixture of hydrated and dehydrated products. The rate of reaction is very impressive
and comparable with recently reported results under microwave irradiation employing
phosphorous pentoxide. The condensation of furfural 8 with malononitrile proceeds at a
faster rate under the present reaction conditions (entry 8, Table 2), unlike in the earlier
reports.
Further, the calcined Ni-Al hydrotalcite was reused without loss of its activity and
selectivity. No reaction occurred, when the reaction was conducted with the filtrate of
14
Abstract
solid catalyst after reaction, indicating that the active ingredient was not leached out of
the solid catalyst.
Thus, calcined Ni-Al hydrotalcite is used as an excellent solid base catalyst for
Knoevenagel condensations. This new solid base catalyst becomes a potential alternate to
soluble bases with the following advantages; a) high catalytic activity under very mild
liquid phase conditions with 100% selectivity for -nitroalkanols, b) easy separation of
the catalyst by simple filtration. c) reaction involves non-toxic and inexpensive materials
d) No side reactions hence waste minimization and e) recycling of the catalyst.
15
Abstract
Table 2: Knoevenagel condensation catalysed by calcined Ni-Al hydrotalcite.
S.No
Starting
material
Product
CHO
CN
H
R
1a R = CN
1b R = CO2Et
1
1
CHO
CN
H
R
2a R = CN
2b R = CO2Et
Cl
2
CHO
O2N
3
NO 2
3
CN
H
R
3a R = CN
3b R = CO2Et
H
R
4a R = CN
4b R = CO2Et
4
CHO
5
CHO
CN
MeO
5
H
97
91
83-84
47-48
3.0
2.0
92
91
161-162
91-92
1.5
2.5
93
95
160-161
169-170
2.0
3.0
90
92
77-79
67-69
2.0
81
___
2.0
2.0
89
86
2.0
90
___
1.5
93
___
2.0
96
93-94
5a CN
CN
H
R
6a R = CN
6b R = CO2Et
OMe
6
CHO
MeO
MeO
OMe
OMe
CN
MeO
H
H
CHO
O
8
114-115
79-80
OMe
O
7
8
2.5
4.0
MeO
6
7
m.p.
OMe
CN
CHO
OMe
OMe
Yield
(%)
Cl
2
4
Time
(h)
7a
CN
CN
R
8a R = CN
8b R = CO2Et
16
Abstract
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18