Enantioselective Aza-Diels Alder reaction catalyzed by clay supported Schiff base complex?

Article abstract of DOI:10.1002/jhet.4155

Clay supported catalysts based on 2- hydroxy naphthaldehyde and amino acids, their copper and titanium complexes have been described. The catalysts were found to be active toward the synthesis of pyrano-, furanoquinolines through Aza-Diels Alder reaction. The catalysts gave good yield and high enantioselectivity. The catalysts were environmentally friendly, economical, synthetically robust and reusable.

Full text of DOI:10.1002/jhet.4155

Enantioselective Aza-Diels Alder reaction catalyzed by clay
supported Schiff base complex1
V Kannan1 and K Sreekumar2*
1. Department of Chemistry, Government College, Kattappana, Idukki District, Kerala, India-685508
2. Department of Applied Chemistry, Cochin University of Science and Technology, Cochin-22, Kerala, India
Corresponding author, footnote: Tel.: +91 484 2862430/2575804; fax: +91 484 2577595
E-mail address: kskpolymer.cusat@gmail.com (K. Sreekumar).
1 Taken in part from the Ph D Thesis of V. Kannan
Abstract
Clay supported catalysts based on 2- hydroxy naphthaldehyde and amino acids, their copper
and titanium complexes have been described. The catalysts were found to be active towards
the synthesis of pyrano-, furanoquinolines through Aza-Diels Alder reaction. The catalysts
gave good yield and high enantioselectivity. The catalysts were environmentally friendly,
economical, synthetically robust and reusable.
Keywords: Peptide metal complex, Clay, Aza-Diels Alder reaction, enantioselective reaction
1. Introduction
Optically active compounds play an important role in several areas of organic and
biological chemistry.[1] Several organic reactions in homogeneous as well as heterogeneous
phases were found to be catalyzed by a wide variety of Schiff’s base complexes. Synthesis of
biologically active molecules has been effectively carried out using Aza Diels Alder
reaction[2]. Chiral metal complexes have been widely used as catalysts for Aza Diels Alder
reaction [3-5]. They are used for the synthesis of heterocyclic compounds containing six
membered rings. Organic reactions utilizing α-amino acids as chiral source are more
prevalent in asymmetric synthesis [6-8]. Peptides have been found useful as asymmetric
catalysts and templates for the controlled formation of Ag nanoparticles [9]. Nevertheless,
Schiff base metal complexes of peptides were scarcely used in asymmetric synthesis due to
complexity in structure and difficulty in preparation [10]. Hydrocyanation reaction has been
was reported to be catalyzed by a titanium (IV)- peptide complex in the homogeneous
medium[11,12]. Schiff base Zn (II) complex derived asymmetric ligands were reported [13]. We
are articulating the idea of anchoring a peptide - metal complex on a readily available and
economical support like clay.
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Normally, it is a difficult task to develop a new chiral catalyst which exhibits Lewis acid
property which can be used for C-C bond formation [14]. Several bioactive compounds of the
alkaloid family were synthesized by reactions catalyzed by imines[15]. The synthesis of such
compounds take place through a three-component reaction mode utilizing aldehydes, amines
and dihydropyran/ dihydrofuran. Aza Diels Alder reaction offers a simple one step method
for the synthesis of six membered heterocycles [16,17]. Several catalysts including transition
[19]
metal complexes [18], chiral Lewis acids of Lanthanide elements
and polyaniline–p-
toluenesulfonate salts [20] have been reported. But, clay supported catalysts for asymmetric
reactions are very few in numbers [21-23]. In our effort to produce cheap supported catalysts[24-
25], we have selected K10 montmorillonite clay as the support. The present manuscript deals
with the synthesis of various furano [3, 2, c] and pyrano [3, 2, c] quinolines through Aza-
Diels Alder reaction catalyzed by clay supported dipeptide- Schiff’s base metal complexes.
2. Experimental
2.1. Materials and Methods
1
Analytical grade reagents and solvents were used. HNMR spectra were recorded on Varian
INOVA-400MHz instrument in CDCl3. IR spectra were obtained from Jasco 4100 FTIR
instrument. Column chromatography was carried out using silica gel (60-120 mesh), which
was supplied by (Merck India Ltd). Reactions were monitored using Thin Layer
Chromatography, which was carried out using pre-coated silica gel plates (Merck 60F-254).
Melting points were determined using the capillary tube method with an electrothermal
apparatus. HPLC analyses were carried out using Shimadzu i Series Prominence 20A. HPLC
or 1HNMR was used to determine diastereomeric ratio and HPLC with chiral column (OJ-H)
was used to determine enantiomeric excess. Thermal stability of the catalysts were
determined using Pyris 6 Diamond model Perkin Elmer instrument under a flow of dry
Nitrogen. The temperature range was from 30oC to 1000◦C. The heating rate was 10◦C/ min.
Varian, Cary 5000 spectrophotometer was used to record Diffuse Reflectance UV-Vis
spectra.
The detailed experimental procedures are given as Supplementary information.
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3. Results and discussion
3.1. Prepartion of the dipeptide ligand
Dipeptide ligands [Scheme 2] were prepared by adopting a procedure reported earlier
[11]
with slight modification
by protecting the amino end of one amino acid by Schiff base
formation using 2-hydroxy-1-naphthaldehyde (Scheme 1) and protecting the acid end of the
second amino acid by ester formation.
HOOC
CH
3
COOH
CHO
CH
OH
N
3
CH
3
Methanol+ethanol(1:9v/v)
rt
HC
HN
2
OH
CH
L-valine
3
2-hydroxy-1-naphthaldehyde
(E)-2-((2-hydroxynaphthalen-1-
yl)methyleneamino)-3-methylbutanoicacid
Scheme 1. Synthesis of amino acid - naphthaldehyde Schiff base
R1
COOH
CH
N
CHO
OH
H2N
COOH
OH
R1
R2
H2N
COOMe
DCC
R1
R2
COOMe
HN
O
CH
N
OH
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Scheme 2. General scheme of the synthesis of dipeptide type ligands.
3.2. Preparation of dipeptide metal complexes
Dipeptide metal complexes were prepared by reacting the dipeptide (Fig 1) and metal salts in
the ratio 1:1 at room temperature using dichloromethane as solvent under N2 atmosphere (Fig
2). The copper complexes were green in colour and titanium complexes were yellow. The
prepared metal complexes were characterized using FT-IR spectra, UV-Visible spectra etc.
DP 2
DP 3
Fig 1. Structures of the dipeptides
3.3. Preparation of K10 clay supported peptide catalyst [26]
The peptide metal complexes were supported on activated K10 clay. The clay was ion
exchanged with sodium. The sodium exchanged clay was reacted with the peptide metal
complexes and form clay supported catalysts (Scheme 3)
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Scheme 3. Proposed structures of the clay supported metal complexes
3.3. FT-IR and UV-Vis spectra of the complexes [26]
“FT- IR spectra of the free ligands and the complexes exhibited a broad band in the region 3300-
3400cm-1, which can be attributed to the stretching vibration of the OH group. The C=N imine
stretching vibration was observed in the region 1619-1655 cm-1 for the free ligand, clearly
indicating the formation of Schiff bases. When the spectra of the complexes were compared with
those of the free Schiff base ligands, the υ(C=N) band observed at 1650cm-1 was shifted to a
lower frequency (1620cm-1), indicating that the imino nitrogen has coordinated to the metal ion.
The negative shift of 30 cm-1 for the band indicated weakening of the C-N bond.[27]
”
Fig 2a
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Fig 2b
Fig 2c
Fig. 2 : FT-IR Spectra of DP3 (Fig 3a), DP3Cu (Fig 3b) and DP3TiP (Fig 3c)
“In the FT-IR spectra of complexes, the asymmetric and symmetric carbonyl stretching
vibration bands are shifted to higher frequency indicating the formation of a linkage between the
metal ion and the carbonyl oxygen.[26,28] Other sets of characteristic absorption bands appear in
the region 1223 and 1521cm-1. These can be assigned to phenolic C-O and amide N-H stretching
vibrations for the free ligands respectively. The phenolic stretching C-O and amide N-H
stretching are shifted to a higher frequency upon complexation implying that the phenolic oxygen
and amide nitrogen on the dipeptide form coordinate bond with the metal ions.[26,29,30] Conclusive
evidence regarding the bonding of the nitrogen and oxygen is provided by the occurrence of
bands at 587-515cm-1(M-N) and 507-424cm-1(M-O)[26, 31] [Fig 2] of Schiff base metal complexes of
DP2 and DP3.”
“The electronic absorption spectra of the metal complexes were recorded in methanol. The
divalent metal complex absorption bands of strong intensity corresponding to C=N chromophore
occur at 200-300 nm. These bands are attributed to π- π* transitions of the extended conjugation
system formed by the benzene ring, phenolic oxygen and imino nitrogen confirming the
formation of Schiff base metal complexes.[26,32] From the Fig.3, it can be observed that only
complexes of copper show peak in this region. The band at, 353, 388, 413 nm have been assigned
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to n- π* transitions of the C=N chromophore, coupled with the secondary band of the benzene
ring.[26,33]
”
-
Fig 3. Electronic spectra of Schiff’s base metal complexes of DP2 and DP3
“DRS spectra of the parent Montmorillonite K10, supported copper complex and supported
titanium complex catalysts are shown in Fig 4. UV-DRS Spectra of the catalysts are characterized
by broad absorption band centered around 400-500 nm in the copper catalysts which are indicated
as violet line and band around 260-270 nm and above 300 nm in the case of titanium catalysts
marked as green line. The parent Montmorillonite K10 shows no absorption band in this region
marked as red line.”
Fig 4. UV-DRS spectra of clay supportedcatalysts derived from DP3
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3.4 IR Spectra of DP3Cu supported clay catalyst
FT-IR spectra of K10DP3Cu catalyst, Fig. 5 showed a weak broad peak in the region 1600 cm-1,
characteristic of carbonyl absorption of the dipeptide.
K10DP3Cu
60
%T
30
500
1000
1500
2000
2500
3000
Wavenumber (cm-1)
Fig 5.FT-IR spectra of K10DP3Cu
3.5 TG/DTA curve of K10DP3Cu
The thermal stability of the Cu catalyst was studied using thermogravimetry. The catalyst
was heated in the temperature range 50-800oC at a heating rate of 10oC/min. Thermogram of the
catalyst showed a weight loss around 230oC which might be due to the loss of the organic part.
The TG/DTA profile of K10DP3Cu is shown in Fig.6.
Fig. 6. TG/DTA of K10DP3Cu
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3.6 Catalytic activity studies
Various catalyst used for the one pot synthesis of furano [3,2,c] and pyranoquinolines by Aza
Diels Alder reaction was compared and the results are given in table 1. It is observed that
recyclable catalysts for this particular reaction is few and are expensive.
Table 1. Comparitive study various catalysts for the synthesis of pyrano[3,2-c] quionoline by
Aza Diels Alder reaction.
Entry
Catalyst
Selectfluor TM
VCl3
Condition Time (h)
Yield [%] Recycle
Ref.
[36]
[34]
[35]
[37]
[38]
[20]
1
2
3
4
5
6
7
CH3CN
CH3CN
50oC, THF
0oC, THF
DCM
3
92
90
93
80
90
81
N
N
N
N
N
Y
2.5
5
SmI2
GdCl3
30
2.5
0.2
Sm(OTf)2
PANI-PTSA
THF
BINOL
CHCl3
[39]
Bronsted acid
catalyst
34
89
N
Optimisation of catalyst concentration was done by selecting benzaldehyde, aniline and
dihydropyran as substrates. The concentrations such as 50, 100, 150, 200, 250mg were taken
and yield of the crude product was noted. It is observed that yield of the product increases as
catalyst concentration increases up to 200mg and further increase of concentration has no
effect on yield and is considered as the optimal concentration for further studies.
Clay supported, Cu and Ti dipeptide complex catalysts were prepared and characterzied.
They were used for the synthesis of furano [3,2,c] and pyranoquinolines by Aza Diels Alder
reaction. Benzaldehyde (1mmol), aniline (1mmol), 3,4-dihydro-2H-pyran or 2,3-dihydrofuran
(1mmol) were used in acetonitrile (10 mL). 200 mg of the clay supported catalyst was used.
The results are summarized in table 2. K10DP3Cu showed better result. It was used for further
studies.
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Table 2. Screening of the catalyst for Aza-Diels Alder reaction
Catalyst
Metal ion
Cu2+
% Yield
48
52
79
68
DP2
Ti4+
Cu2+
Ti4+
DP3
The Aza-Diels Alder reaction was conducted with K10DP3Cu. During the reaction, imines were
generated in situ from aldehydes and amines. They reacted easily with dihydropyran to afford
pyrano[3,2-c]quinolines in one pot. The pre-formation of imines was not an essential condition. The
reaction did not occur in the absence of the catalyst. In the yield of the products, there was no
considerable influence of the electronic properties or steric hindrance of the substituents on the
aldehydes. Ring-fused [3,2-c] quinolines were obtained in good to excellent yield. High
enantioselectivity was observed. General scheme of the reaction is given in scheme 4.
Scheme 4.General scheme of Aza-Diels Alder reaction
Different solvents were used in the reaction with Benzaldehyde, aniline and dihydropyran using
K10DP3Cu (200 mg) as catalyst. The results are summarized in table 3. Acetonitrile was found
to be the best solvent. In order to validate the scope of the reaction, it was conducted using
different amines and aldehydes. The results are presented in table 4. The reaction proceeded in
one pot in a three component mode which resulted in the formation of the corresponding pyrano/
furano [3,2-c] quinolines.
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Table 3.Effect of solvents on Aza-Diels Alder reaction
Sl.No
Solvent
CHCl3
%Yield of the product
1
2
3
4
76
78
82
84
C2H5OH
CH3OH
CH3CN
5
H2O
79
Reaction condition: Benzaldehyde (1mmol), aniline (1 mmol), 2, 3-dihydropyran (1 mmol), 200 mg
catalyst, at room temperature for 12h under N2 atmosphere
Table 4.Aza-Diels Alder reaction of various substrates
Yield
Entry RCHO
RNH2
Olefin
M.poC ee(%)b
(%)a
79
1
2
3
Benzaldehyde
Aniline 3,4-dihydropyran
Aniline 3,4-dihydropyran
Aniline 3,4-dihydropyran
120
180
163
83
99
82
3-Nitrobenzaldehyde
4-Chlorobenzaldehyde
68
71
4-Bromo
4
5
Benzaldehyde
3,4-dihydropyran
aniline
78
76
147
145
81
87
Thiophene-2-
carboxaldehyde
Aniline 3,4-dihydropyran
6
7
4-Methoxybenzaldehyde
Benzaldehyde
Aniline 3,4-dihydropyran
Aniline 2,3-dihydrofuran
81
78
-
83
81
108
4-Bromo
8
9
3-Nitrobenzaldehyde
3-Nitrobenzaldehyde
2,3-dihydrofuran
aniline
64
62
184
159
89
73
Aniline 2,3-dihydrofuran
Reaction condition: Benzaldehyde (1mmol), aniline (1 mmol), 2, 3-dihydropyran (1 mmol), 200 mg
catalyst, at room temperature for 12h under N2 atmosphere
aIsolated yield of purified product
bDetermined by HPLC with chiral OJ-H column
1
“The products were characterized by determining the m.p and comparing the IR. HNMR
1
spectra were used to establish the cis ring fusion. In the HNMR spectra, for the signals at
~5ppm, the coupling constant (J4a, ) = 5.2 Hz is small and typical for a guache confirmation of
5
the protons, consistent with all cis-configuration of the hydrogen atoms 4a, 5 and 10b. The
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coupling constant (J4a, 10b) in all products (2.2-2.9 Hz) leads to the cis fusion of the pyran-and
quinoline rings.”
Recycling studies
When the reaction was completed, the catalyst was filtered, washed several times with acetone,
methanol and ethyl acetate. It was dried at 100oC for 1h and reused. There was a slight decrease
in the activity of the catalyst after each cycle. The results of recycling studies are summarized in
Fig. 7. The decrease in yield of product may be ascribed to leaching of bulkier metal complex
after each cycle of reaction.
Fig 7.Recycling studies of the catalyst
Reaction condition: Benzaldehyde (1 mmol), aniline (1 mmol), 3, 4-dihydropyran (1 mmol), Catalyst 200 mg,
Solvent: acetonitrile (5 mL) Time: 12h, RT
aIsolated yield
4. Conclusions
K10 clay supported copper and titanium catalysts were synthesized efficiently with dipeptide
ligands obtained from natural amino acids. Their catalytic activity was investigated in
Asymmetric Aza Diels alder reaction. The amount of catalyst required was low, good yields and
high enantioselectivity were obtained in all the cases studied. The catalyst is recyclable.
Acknowledgement
We thank CSIR and UGC Government of India for fellowships. SAIF CUSAT and NMR
Research Centre IISc Bangalore are acknowledged for various spectral analyses.
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