New synthesis of β -anilinochalcones by regioselective oxidation of β -anilinodihydrochalcones using iodine-DMSO

Article abstract of DOI:10.1080/00397911.2012.667490

β-Anilinodihydrochalcones readily undergo oxidation α to the carbonyl group region in the presence of a catalytic amount of iodine in dimethyl sulfoxide at 130 °C in good yield. Oxidation of allyloxy-substituted β-anilinodihydrochalcones to β-anilinochalcones is a preferred reaction over deallylation.

Full text of DOI:10.1080/00397911.2012.667490

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A New Synthesis of β-Anilino-Chalcones by
Regioselective Oxidation of β-Anilino-Dihydro-
Chalcones using Iodine-DMSO
Beena R. Nawghare a & Pradeep D. Lokhande a
a The Centre for Advanced Studies, Department of Chemistry , University of Pune , Pune 411
007 , India
Accepted author version posted online: 27 Dec 2012.Published online: 27 Dec 2012.
To cite this article: Synthetic Communications (2012): A New Synthesis of β-Anilino-Chalcones by Regioselective Oxidation of
β-Anilino-Dihydro-Chalcones using Iodine-DMSO, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2012.667490
To link to this article: http://dx.doi.org/10.1080/00397911.2012.667490
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A New Synthesis of β-Anilino-Chalcones by Regioselective Oxidation of β-Anilino-
Dihydro-Chalcones using Iodine-DMSO
Beena R. Nawghare1, Pradeep D. Lokhande1
1The Centre for Advanced Studies, Department of Chemistry, University of Pune, Pune
411 007, India
Fax: +91(020)25691728, Email: pdlokhande@chem.unipune.ernet.in
Abstract
β-anilino-dihydro-chalcones readily undergo oxidation at α-to carbonylgroup region in
presence of catalytic amount of iodine in dimethyl sulphoxide at 130 °C in high yield.
Oxidation of allyloxy substituted β-anilino-dihydro-chalcones to β-anilino-chalcones is a
preferred reaction over deallylation.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
R3
R3
O
HN
O
O
I2 (0.2 mmol)
130 °C, 30 min
HN
O
DMSO,
R1
R1
60-74%
R2
R2
2
1
KEYWORDS: β-anilino-chalcone, dehydrogenation, iodine, dimethyl sulphoxide
INTRODUCTION
β-enaminones are important precursors of a wide variety of heterocycles[1] and
pharmaceutical compounds.[2] They exhibits anti-epileptic,[3]molluscicidal, and larvicidal
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activities[4] and employed as an intermediates for the synthesis of naturally occurring
alkaloids.[5] β-Enamino ketones[6] were widely applied in the functional group
transformation in the field of organic synthesis, including β-alkoxyvinyl ketones
enamination,[7] 1,2-aryl migration,[8] 1,3-dicarbon enamination,[9]imidoyl chlorides with
lithium enolates of alkyl propanoates to β-enaminones,[10] lithiateenamine acylation[11]
and SonochemicalBlaise reaction.[12] These synthetic routes involve cyclic β–enaminones
as well as β-anilinochalcones synthesized in the present work.
The most well-known and exploited route to β-enaminones involves the direct
condensation of β-dicarbonyl compounds with amine at reflux in an aromatic solvent
with azeotropic removal of water.[13] Several improved procedures have been reported
including reaction of amines and 1,3-dicarbonyl compounds supported on silica with
microwave irradiation,[14] clay montmorillonite K10/ultra-sound[15] or NaAuCl4,[16]
bismuth(III) trifluoroacetate,[9b] erbium triflate[17] or zirconium(IV) chloride,[18]
cyclization of amino acids,[19] reductive cleavage of silylisoxazoles,[20] the direct
condensation of primary amines and β-diketones in water.[21]These processes suffer from
the limitations such as drastic reaction conditions, low yields tedious work-up
procedures, co-occurrence of several side reactions and need of purification of adducts.
Another route for the synthesis of β-enaminones is from chalcones and anilines. They
react to give β-amino ketones[22] which can be converted to β-enaminones. But this
method increases number of steps. That means to obtain β-enaminones oxidation of β-
amino ketones is the only option.
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K. C. Nicolaou et al. reported the dehydrogenation of aldehydes and ketones to α, β-
unsaturated carbonyl compounds by using IBX.[23] Here, proper care is required in
handling hazardous o-iodoxybenzoic acid. Although synthesis of β-enamino ketones was
reported from endoglucal via hypervalent iodine,[24] dehydrogenation of chalcone by
using iodine in dimethylsulphoxideis not reported yet. Thus, to report high yielding and
simple method for the synthesis of β-enamino ketones is of immense importance.
RESULT AND DISCUSSION
β-Anilino-dihydro-chalcones were prepared as a starting material for the synthesis of β-
anilino-chalcones by Mannich reaction. Ammonium chloride reagent has been used in
various reactions. It effectively promotes multi component reactions for the synthesis of
many heterocyclic compounds.[25]
Flavones were synthesized from 2’-allyloxy-chalcones by allyl deprotection procedures
using iodine in dimethyl sulphoxide reagent.[26] In this reaction allyl group is first
deprotected and 2’-allyloxy-chalcones then oxidatively cyclized to flavones. Allyloxy-β-
anilino-dihydro-chalcones were subjected to the same reaction condition to get 4-amino-
flavones. For the synthesis of 4-amino-flavone derivatives (5i-p)it is necessary to have
allyloxy-β-anilino-dihydro-chalcones (4i-p). Hence we protected salicylaldehyde by allyl
group and then subjected to Mannich reaction condition (Scheme 1). It was smoothly
converted to allyloxy-β-anilino-dihydro-chalcones (4i-p). First time we reported the
preparation ofMannich type bases by using allyloxy salicylaldehydes (2).
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Earlier, deallylation study has been done for various substrates by using iodine in
dimethylsulphoxide at 130°C.[26,27] Similarly same reagent was applied for catalytic
dehydrogenation in nitrogen and oxygen containing heterocycles.[26,28,29] Allyloxy-β-
anilino-dihydro-chalcones (4i-p) could be converted to 4-amino-flavones (5i-p) by using
I2-DMSO reagent[26] in one step. The reaction of allyloxy-β-anilino-dihydro-chalcones
(4i-p) with (0.2 mmol) iodine in dimethyl sulphoxide at 130°C was completed in 30
minutes. In the 1HNMR spectra of the product, the protons of allylic functionality (δ 4.63,
5.31, 6.01) remain intact but protons CH2 (δ3.14) and CH (δ 5.27) was disappeared.A
new proton was appeared in the aromatic region. In GCMS single product was observed
and in MS, the mass of product was less by 2 than the substrate. This has confirmed the
oxidation of a substrate at α-to carbonyl group region. That means allyloxy-β-anilino-
dihydro-chalcones (4i-p) has been oxidized to allyloxy-β-anilino–chalcones (6i-p). It was
observed that catalytic amount of iodine in dimethyl sulphoxide was unable for the
deprotection of allyl group. Instead of deallylation, oxidation was observed. In earlier
study it was observed that deallylation takes place by iodine in dimethylsulphoxide at
130°C however, in present work under the same reaction condition dehydrogenation of β-
anilino-dihydro-chalcone is preferred over deallylation. For detail study, the reaction of
allyloxy-β-anilino-dihydro-chalcone (4i) with iodine in dimethyl sulphoxide to give
allyloxy-β-anilino- chalcone (6i) is selected as an appropriate model reaction. We
optimized catalyst loading using different amount of catalyst (Table I).
Initially allyloxy-β-anilino-dihydro-chalcone (4i) was heated with 0.1 mmol iodine in
dimethyl sulphoxide. There was no reaction below 130°C. Temperature of reaction
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mixture was increased to 130°C. The product was formed in 30 minutes but starting also
observed on TLC plate. Then reaction was performed with 0.2 mmol of iodine at 130°C.
From TLC it was confirm that the reaction completes in 30 minutes.0.2 mmol of iodine
was sufficient to give desired product (6i) in high yield. No significant improvement in
the yield was observed on increasing the catalyst amount from 0.2 mmol to 1 mmol. On
increasing the temperature up to 140°C, the substrate was decomposed. No change in the
product was observed after using the catalyst in excess amount and increasing the time
for 1-2 hours. After standardizing the reaction conditions, various substrates of β-anilino-
dihydro-chalcones (4a-p) were allowed to react with iodine in dimethylsulphoxide to
give β-anilino-chalcones (6a-p) (Scheme 2). The results are summarized in Table II. This
reaction was not pursued further for the preparation of 4-amino-flavones (5i-p). The
study of 4-amino flavone synthesis by changing the reaction condition is in progress.
The formation of allyloxy-substituted-β-anilino-chalcones (Table II, entry 9-16) may
due to the interaction of anilino group with iodine. Such kind of oxidation was observed
in the conversion of pyrazolines to pyrazoles[29] and oxidation of tetrahydroindazole to
dihydro indazole.[30] Regioselectivity in dehydrogenation at α-to carbonyl group region
(i.e. CH2-CH) to CH=C instead of CH=NH to C=N was observed. The proposed
mechanism of oxidation is given in the Scheme 3.
CONCLUSION
We have successfully synthesized allyloxy-β-anilino-dihydro-chalcones of three
components such as acetophenones, allyloxy salicylaldehydes and anilines in presence of
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ammonium chloride in methanol. A simple and efficient method was presented for
oxidation of β-anilino-dihydro-chalcones to β-anilino-chalcones using I2-DMSO reagent.
However, regioselective oxidation of allyloxy substituted β-anilino-dihydro-chalcones at
α-to carbonyl group regionis a preferred reaction over deallylation.
EXPERIMENTAL
TLC was performed on E-Merck precoated 60 F254 plates and the spots were rendered
visible by exposing to UV light and iodine. Melting points were determined with an
Electro thermal model 9100 apparatus and are uncorrected. IR spectra were recorded on a
Shimadzu 8000 spectrophotometer. The 1H and 13C NMR spectra were recorded on
Varian spectrometer. Chemical shifts (δ) are reported in ppm and with reference to
tetramethyl silane as internal standard. Mass spectra (GCMS) were recorded on a
Shimadzu Q 5050 spectrometer.
General Procedure For The Oxidation Of Β-Anilino-Dihydro-Chalcones To Β-
Anilino-Chalcones By Using I2-DMSO Reagent
To a solution of β-anilino-dihydro-chalcones (1 mmol) in DMSO (5 ml) was added
iodine (50.8 mg, 0.2 mmol) and the reaction mixture was heated in an oil bath at 130°C
for 30 min. After cooling, iodine was removed by washing with a saturated solution of
sodium thiosulphate and water. The product was then extracted with ethyl acetate and
dried over Na2SO4 and solvent was evaporated. The product (6a-p) was purified by
column chromatography (hexane/ethyl acetate, 9:1).
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Spectral Data Ofselected Compounds
3-(2-Allyloxyphenyl)-1-(4-Chlorophenyl)-3-(Phenylamino) Propen-1-One (6j)
IR (KBr): 3383, 3030, 1674, 1525 cm-1; 1H NMR (300 MHz, CDCl3): δ=8.00-7.97 (m,
1H, aromatic-H), 7.96-7.82 (m, 2H, aromatic-H), 7.56-7.41 (m, 5H, aromatic-H), 7.38-
7.33 (m, 1H, aromatic-H), 7.27 (m, 1H, C-H), 7.15-6.96 (m, 4H, aromatic-H), 6.12-6.01
(m, 1H, CH), 5.31 (dd, J = 17.4, 10.5 Hz, 2H, CH2), 4.63 (d, J = 1.5 Hz, 2H, CH2); 13C
NMR (300 MHz, CDCl3): δ=189.99, 69.15, 40.72; MS(m/z): 389 (M+ ion); Anal. calcd
for C24H20ClNO2: C, 73.94; H, 5.17%. Found: C, 73.79; H, 5.27%.
3-(2-Allyloxyphenyl)-1-Phenyl-3-(3-Chlorophenylamino) Propen-1-One (6k)
IR (KBr): 3365, 2924, 1683, 1599 cm-1; 1H NMR (300 MHz, CDCl3): δ=8.05-7.96 (m,
2H, aromatic-H), 7.83 (d, J = 7.8, 1H, aromatic-H), 7.56-7.42 (m, 5H, aromatic-H), 7.36-
7.30 (m, 2H, aromatic-H), 7.26-7.19 (m, 1H, C-H), 7.06-6.96 (m, 3H, aromatic-H), 6.14-
6.02 (m, 1H), 5.32 (dd, J = 17.4, 10.5 Hz, 2H, CH2), 4.66 (d, J = 5.4 Hz, 2H, CH2); 13C
NMR (300 MHz, CDCl3): δ=189.74, 69.10, 40.64; MS(m/z): 389 (M+ ion); Anal. calcd
for C24H20ClNO2: C, 73.94; H, 5.17%. Found: C, 73.68; H, 5.32%.
Complete experimental and spectral details are available online the Supplementary
Information.
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Table I Temperature Effect andQuantity of iodine
Entry Compound
Iodine (mmol)
Temperature (°C) Time (h) Yield
(%)a,b
1
2
3
4
5
4i
4i
4i
4i
4i
0.1
0.1
0.2
0.5
1.0
Below 130
130
0.5
0.5
0.5
0.5
0.5
0
35
67
68
68
130
130
130
aIsolated yields of the product bProducts are characterized by spectral analysis
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Table II Oxidation of β-anilino-dihydro-chalcones by using I2-DMSO reagent.
Entry
4
Starting (4)
6
Product (6)
Yield
(%)a,b
O
O
HN
HN
1
4a
6a
65
O
O
Cl
HN
Cl
HN
2
3
4b
4c
6b
6c
67
Cl
Cl
O
O
HN
HN
74
70
64
Cl
Cl
O
O
Cl
Cl
HN
HN
4
5
4d
4e
6d
6e
Cl
O
Cl
O
HN
HN
Cl
Cl
O
O
Cl
HN
Cl
HN
6
4f
6f
63
O
O
Cl
Cl
HN
HN
7
8
4g
4h
6g
6h
61
60
O
O
Cl
Cl
Cl
Cl
HN
HN
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O
O
HN
HN
9
4i
6i
67
68
O
O
O
O
Cl
HN
Cl
HN
10
4j
6j
O
O
Cl
Cl
O
O
HN
HN
11
12
13
14
4k
4l
6k
6l
73
71
68
62
O
O
Cl
Cl
O
O
Cl
HN
Cl
HN
O
O
Cl
Cl
O
O
HN
HN
4m
4n
6m
6n
O
O
Cl
Cl
O
O
Cl
Cl
HN
HN
O
O
O
O
Cl
Cl
HN
HN
15
16
4o
4p
6o
6p
70
67
O
O
O
O
Cl
Cl
HN
Cl
Cl
HN
O
O
aIsolated yields of the product bProducts are characterized by spectral analysis
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Scheme 1 Synthesis of β-anilino-dihydro-chalcones
R3
O
NH2
O
HN
CHO
2
OR
CH3
NH4Cl (0.5 mmol)
R1
R3
R1
R2
MeOH, r.t.
80-95%
RO
R2
1
3
4a-p
I2 (1mmol),
DMSO
R = H, CH2CH=CH2
130 °C, 30 min
R3
HN
O
R1
R2
5i-p
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Scheme 2 Oxidation of β-anilino-dihydro-chalcones by using I2-DMSO reagent.
R3
R3
O
HN
RO
O
HN
I2 (0.2 mmol)
130 °C, 30 min
DMSO,
R1
R1
60-74%
RO
R2
R2
4a-p
R = H, CH2CH=CH2
6a-p
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Scheme 3 Plausible mechanism of oxidation of β-anilino-dihydro-chalcones by using I2-
DMSO reagent.
O
O
O
H
R2
R1
R2
R1
I
R2
H
R1
I2 (0.2 mmol)
130 °C
DMSO,
I
O
O
HN
I
NH
O
NH
R3
R3
R3
O
O
H
R2
R1
I
R2
R1
-HI
O
NH
O
NH
R3
R3
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