One-pot synthesis of functionalized isoxazole-thiolane hybrids via Knoevenagel condensation and domino sulfa-1,6-Michael/intramolecular vinylogous Henry reactions

Article abstract of DOI:10.1039/c5ra16721c

One-pot synthesis of highly functionalized tetrahydrothiophene (thiolane) derivatives conjugated with biologically useful isooxazole are reported via the Knoevenagel condensation followed by domino sulfa-1,6-Michael/intramolecular vinylogous Henry reactio

Full text of DOI:10.1039/c5ra16721c

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One-pot synthesis of functionalized isoxazole-thiolane hybrids via
Knoevenagel condensation and domino sulfa-1,6-Michael /
Received 00th January 20xx,
Accepted 00th January 20xx
intramolecular vinylogous Henry reactions
†
Sakkani Nagaraju,a Neeli Satyanarayana,a Banoth Paplal,a Anuji K. Vasu,b Sriram Kanvah,b
DOI: 10.1039/x0xx00000x
Balasubramanian Sridhar,c Prabhakar Sripadid and Dhurke Kashinatha*
www.rsc.org/
One-pot synthesis of highly functionalized tetrahydrothiophene nucleophile) for the tandem Michael–Henry or Michael–
(thiolane) derivatives conjugated with biologically useful isooxazole Michael reactions resulting in to 3,4-disubstituted
are reported via the Knoevenagel condensation followed by domino tetrahydrothiophenes.9a Similar strategy was adopted by
sulfa-1,6-Michael / intramolecular vinylogous Henry reactions of Southern9b,c and Ramström9d groups for the preparation of
aldehydes, 1,4-Dithiane-2,5-diol and 3,5-dimethyl-4-nitroisoxazole. substituted nitro-thiophenes starting from β-nitrostyrenes.
From the base and solvent screening, it was found that piperidine
(30 mol%) and ethanol are best suitable conditions giving the
desired products with >95% yields in 2-2.5 h overall reaction time.
O
EtHN
COOH
COOH HO
NH
HO
N
NH2
CH3
AMPA
N
i-Pr
OH
Isoxazole moiety is present in natural molecules like
AMPA,1a Ibotenic acid.1b The synthetic derivatives of isoxazole
are known as inhibitors of Heat Shock Protein90 activity,2a
initiators of neurogenesis,2b broad spectrum antibiotics,2c
antiviral agents2d non-steroidal anti-inflammatory drugs2e and
immunosuppressive agents.2f The tetrahydrothiophene is part
of natural glucosidase inhibitor (salacinol),3a Cholecystokinin
type-B receptor antagonist (tetronothiodin)3b and used for the
O
N
O
N
O
NH2
O
S
HO
Ibotenic acid
(Ionotropic Glu receptor (Psycho active)
(Neuroregenerative)
CH3
NVP-AUY922
(HSP90 inhibitor)
antagonist)
N
CO2H
CH3
CH3
R
O
O
O
N
OH HN
N
O
S
O
N
HN
O
CH3
Cl
N
H
H
N
F
N
O
S
O
CH3
O
O
O
Penicillin hybrids
(antibiotic)
Isoxicam
(NSAID)
(Antiviral)
development of HIV and hepatitis
thiophene-isoxazole molecules also used for pulmonary
hypertension (Sitasentan TBC 11251) and as
B
inhibitors.3c The
O
N
CF3
R
S
OH
NH
O
N
OH
OSO3
O
O
phosphodiesterase 4B inhibitors.4 Along with these, isoxazole
can be used for the preparation of carboxylic acids5 and
thiophene is extensively used in medicinal and materials
chemistry.6
NH
Ph
Cl
S
HO
N
N
HO
OH
CH3
O
HO
OH
Salacinol
(HIV and Hepatitis B
inhibitors)
Leflunomide
(immunosuppressive)
(Nicotinic receptor
modulator)
(Glucosidase inhibitor)
Me
O
Dimeric α-mercaptoacetaldehyde (1,4-Dithiane-2,5-diol, 1)
R1
Me
H3C
was used for the thiazole synthesis by Gewald and co-workers
in 1966.7 Later, Belleau (1984)8a and Spino (1995)8b groups
used this molecule for the preparation of cyclic thia derivative
via Michael type addition and intramolecular Aldol reactions
which was further used for the diene generation. In 2006
Pollini and co-workers exploited the bifunctional nature of 1,4-
HO
Cl
O
R2
Ar
N
O
S
O
N
O
HO
H
O
S
R3
N
(PDE 4B inhibotors)
H
O
Me
HOOC
O
O
S
O
N
O
O
H3C
S
OH
CH3
O
Tetronothiodin
Sitasentan TBC 11251
(Cholecystokinin type-B (Pulmonary hypertension)
receptor antagonist)
O2N
S
Dithiane-2,5-diol
(1) (-CHO as electrophile and –SH as
CH3
O2N
R
HO
S
CHO
Isoxazole-thiolane hybrids
(Present study)
N
H3C
S
1
OH
O
2
R
3
Compounds used in present study
Figure-1. Different biologically active molecules with substituted isoxazole, tetrahydro
thiophene and isoxazole-thiophene moieties and present investigation
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Journal Name
S. No. Solvent
Base
Reaction time Isolated Yield
The bifunctionality of 1,4-Dithiane-2,5-diol (1) is very much
(%)a
exploited in combination with
α,β-unsaturated carbonyl
(30 mol%)
(h)
compounds and their derivatives. In this context, Tang et al,
reported the domino thia-Michael/Aldol condensation
reactions using proline-based organocatalyst with good
enantioselectivity.10a After this report, many methods
appeared in the literature for the construction of complex
/spirocyclic molecules using chalcones derivatives (in presence
of chiral squaramide as catalyst,10b-d and catalyst free
conditions10e,f), oxindoles [(squaramide catalyst; via [3+2]
annulation),11a N,N’-dioxide–nickel(II) complex,11b], and
isoindigos.11c Along with these, recently cyclopropane
1
2
3
4
5
6
7
8
9
Water
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
10
90
Acetonitrile
Chloroform
Dichloromethane
Methanol
24
5
70
99
60
85
87
70
65
50
65
50
60
65
45
70
60
75
80
70
76
60
85
99
24
24
10
24
24
24
24
24
24
24
24
24
24
24
10
24
24
24
5
Ethanol
Dimethylsulfoxide
N,N-Dimethylformamide
Water
10 Chloroform
11 Dichloromethane
12 Methanol
13 Ethanol
DBU
derivatives11d-f
N-substituted
azomethine
imides
imine
(via
(via
[3+2]-
[3+3]-
DBU
cycloaddition),12a-c
DBU
cycloaddition),13a alkynols,13b hydroxylamines,13c and vinyl
azides13d has also been used for the construction of thiolane
rings.
DBU
14 Water
TEA
15 Chloroform
16 Dichloromethane
17 Methanol
18 Ethanol
TEA
TEA
3-methyl-4-nitro-5-styrylisoxazole (2) in which the two
TEA
double bonds are in conjugation with Nitro group can be used
as cinnamate equivalent. The 1,6-Michael addition of 3-
methyl-4-nitro-5-styrylisoxazole is a well-known concept.14
However, the formation of two new bonds with Michael
addition followed by [2+3]-cyclo-addition is less explored in
the literature.15 Moreover, there are no reports with the
formation of C-C, C-S bonds and [2+3]-annulation in
intramolecular fashion (One-pot synthesis).
TEA
19 Water
Piepridine
Piepridine
Piepridine
Piepridine
Piepridine
20 Chloroform
21 Dichloromethane
22 Methanol
23 Ethanol
15 min
Table-1. Optimization of reaction conditions for Sulfa-1,6-Michael/intramolecular
vinylogous (Henry) reaction; Reaction conditions: aAll the reactions were
performed at 100 mg scale of isoxazole styrene derivative using 30 mol% of base
Considering the importance of isoxazole and thiophene
moieties, growing applications of
α-mercaptoacetaldehyde 4
From the above studies, it is clear that the reaction is
successful in chloroform + DABCO and ethanol + piperidine
combinations (Table 1; entries 3 and 23). After optimization of
the reaction conditions, one-pot synthesis of isoxazole-
and in continuation of our efforts of developing greener
synthetic methods,16 here in we report one-pot synthesis of
functionalized isoxazole-thiolane hybrids. Towards this, the
mercaptoacetaldehyde was reacted with isoxazole derivative
in presence of DABCO (30 mol%) in water to give the
isoxazole-thiolane hybrid (with three consecutive sterogenic
α-
4
thiolane hybrid
5 was attempted starting from corresponding
3
aldehyde. However, it was observed that the formation of
styrene derivative in less yield [> 45% (in water and chloroform
medium)]. Whereas, in ethanol + piperidine combination, the
reaction went to completion yielding desired isoxazole-
5
centres) in 90% yield (Scheme-1). After confirmation of the
product (see ESI for spectral data), attempts were made to
optimise the reaction conditions using different combinations
of solvents and bases (organic and inorganic) and the best
results are given in Table-1.
thiolane hybrid
5
in quantitative yield (with in situ formation of
) as shown in Scheme-2.
isoxazole-styrene as intermediate
3
Scheme-1. Sulfa-1,6-Michael
/ intramolecular vinylogous (Henry) reactions of 1,4-
Scheme 2. One-pot Knoevenagel condensation followed by sulfa-1,6-Michael / direct
vinylogous (Henry) reactions of 1,4-dithiane-2,5-diol (1) and isoxazole based
nitrostyrene (4)
dithiane-2,5-diol (1) and isoxazole based nitrostyrene (4)
From the mechanism, we assume that the generation of
isoxazole-styrene
which react with mercaptaldehyde
monomer) via sulfa-1,6-Michael/intramolecular vinylogous
3
is a result of Knoevenagel condensation
4
(in situ generated
(Henry) reactions to give the desired cyclised product
2).
5 (Figure
2 | J. Name., 2012, 00, 1-3
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compound 5k as shown below (Figure 4; for the experimental
OH
S
+
OH
details see ESI). The ORTEP diagram (CCDC 1426687) indicating
N
H
S
H
O
N
H
that the protons on C1 and C4 are positioned in anti
-
1
O
H3C
NO2
O
CHO
H3C
configuration.
N
O
H3C
NO2
N
H
SH
N
N
SH
O
N
+
O
CH3
O
2
R
Ar
3
4
H2O
R
[Thia 1,6-Michael addition]
N
H
H
S
O
N
H3C
O
N
O
H3C
OH
O
N
NO2
O
S
Figure-4. ORTEP diagram of compound 5k; A view of AY15, showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms
are represented by circles of arbitrary radii.
R
5a-5t
R
[Vinylogous Henry reaction]
Figure-2. Plausible reaction mechanism for sulfa-1,6-Michael
/ direct vinylogous
(Henry) reactions of 1,4-dithiane-2,5-diol (1) and isoxazole based nitrostyrene (4)
After successful demonstration of one-pot synthesis of
isoxazole-thiolane hybrids, focus was shifted towards the
preparation of more complex derivatives. Thus, the
Subsequently, various aromatic (with electron donating
and electron withdrawing groups) and heteroaromatic
aldehydes were reacted (65oC, 2 h) with 3,5-dimethyl-4-
nitrobutadienes (7a-7b) (in situ) and oxindole-based isoxazole
12c
nitrostyrene (
reaction followed by mesylation-elimination and reacted with
-mercaptoacetaldehyde under optimized conditions to give
9)
were prepared using vinylogous Henry
nitroisoxazole (
1) in presence of catalytic amount of piperidine
(30 mol%) to give the functionalized nitrostyrene derivatives
α
4
(in
situ)
which
were
then
(RT, 5-15 min) to give the
5t) in excellent
treated
with
α-
functionalized isoxazole-thiolane hybrids (8a
-8b and 10) in
mercaptoacetaldehyde
4
good yields (Schemes 3 and 4).
functionalized isoxazole-thiolane hybrids (5b
-
H3
C
NO2
CH3
yields (Figure-3). Though the yields are very good, the
substrate dependent reactivity was observed for completion of
the reaction. The substrates with electron withdrawing groups
require shorter reaction times than the substrates with
electron donating groups as summarized in Figure-3.
N
O
N
CH3
O
2
Piperidine (30 mol%)
NO2
+
EtOH, 65 o
2 h
C
R
O
7a
7b
; R = H
(Step-i)
; R = OCH3
R
OH
S
6a
6b
; R = H
; R = OCH3
N
N
O
O
H3
C
H3C
N
N
OH
N
OH
O
O
O
S
OH
H3C
O2
H3C
O2
H3C
OH
OH
OH
1
O2
N
O2N
H3CO
RT, 45 min
S
S
N
N
O2N
H3CO
S
S
S
(Step-ii)
H3CO
H3CO
H3
C
H3CO
OCH3
(95%)
OCH3
OCH3
(90%)
N
O
5b
5c
5d
5e
5f
H3C
O2N
(96%)
(95%)
(95%)
OH
S
N
N
O
O
H3C
O2
H3
C
OH
N
O
N
O
OH
N
O
H3C
O2
H3
C
H3C
OH
OH
OH
N
O2
N
S
N
S
O2N
O2N
R
S
S
S
8a
8b
; R = H (90%)
OH
OCH3
5g
n-Pr
(H3C)2
N
; R = OCH3 (85%)
OH
(90%)
OH
5i
Br
5h
5j
5k
(90%)
(90%)
(90%)
(98%)
O
Scheme-3. One-pot Knoevenagel condensation followed by sulfa-1,6-Michael / direct
vinylogous (Henry) reactions of 1,4-dithiane-2,5-diol (1) and isoxazole based
nitrostyrene (7a-7b)
N
N
O
O
H3
C
H3C
OH
N
N
OH
N
O
O
H3
C
H3C
H3
Cl
C
OH
OH
OH
O2
N
O2
N
S
O2
N
O2N
S
O2
N
S
S
S
Cl
O2
N
NO2
5o
NO2
(99%)
CH3
Cl
NO2 OH
O2N
5l
5m
5n
5p
(98%)
(99%)
(99%)
(99%)
CH3
CH3
H3C
N
N
Cl
O
O
N
H3C
NO2
OH
H3
C
NO2
N
S
OH
OH
N
N
O
O
N
O
O
O
OH
OH
S
pyperidine (30 mol%)
EtOH, RT, 15 min
OH
H3C
O2
N
O2N
OH
O
O
S
+
S
O
N
N
S
S
O2
N
S
N
N
S
O
S
N
N
Bn
Bn
10 (95%)
Ph
5t
Ph
9
1
5q
5r
5s
5u
(99%)
(97%)
(98%)
(99%)
(99%)
Scheme-4. Synthesis of spiro ixindole based isoxazole-thiolane hybrid (10)
Figure-3. Different isoxazole-thiolane hybrids (5b-5t)
Towards establishing the stereochemistry of the resulting
products, the X-ray crystallographic data was obtained for the
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Journal Name
Scientific Publishing Company Pvt. Limited, 2012; (c) Igor F.
Perepichka, Dmitrii F. Perepichka (Ed), Handbook of
Thiophene-Based Materials: Applications in Organic
Later, compound
(
5k
)
was used for further
functionalization using
m-CPBA in dichloromethane to give the
sulfone 11 in 95% yield (Scheme 5).
Electronics and Photonics, Vol I & II, John Wiley & Sons, 2009
.
7
8
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Scheme-5. Functionalization of compound 5k to sulfone 11
In conclusion, we have demonstrated an efficient method for
one-pot synthesis of functionalized isoxazole-thiolane hybrids
under mild conditions with very good yields. The derivatives
reported here can be used for biological applications. Also,
aromatization followed by hydrolysis of isoxazole will give
trisubstituted thiophene derivatives with carboxylic acids
which can act as anchoring group for potential applications as
materials.
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One-pot synthesis of functionalized isoxazole-thiolane hybrids via
Knoevenagel condensation and domino sulfa-1,6-Michael / intramolecular
vinylogous Henry reacꢀons†
Sakkani Nagaraju,a Neeli Satyanarayana, a Banoth Paplal, a Anuji K. Vasu,b Sriram Kanvah,b Balasubramanian
Sridhar,c Prabhakar Sripadid and Dhurke Kashinatha*
aDepartment of Chemistry, National Institute of Technology, Warangal-506 004, India
e-mail: kashinath@nitw.ac.in; kashinath.dhurke@gmail.com
Tel. +91-870-2462677; FAX No. +91-870-2459547
bDepartment of Chemistry, Indian Institute of Technology, Gandhinagar, Ahmedabad, India
cX-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology
Hyderabad - 500007, India.
dNational Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad - 500007,
India
One-pot synthesis of highly functionalized tetrahydrothiophene (thiolane) derivatives conjugated with
biologically useful isooxazole are reported via the Knoevenagel condensation followed by domino sulfa-1,6-Michael /
intramolecular vinylogous Henry reactions of aldehydes, 1,4-Dithiane-2,5-diol and 3,5-dimethyl-4-nitroisoxazole. From the
base and solvent screening, it was found that piperidine (30 mol%) and ethanol are best suitable conditions giving the
desired products with >95% yields in 2-2.5 h overall reaction time.