Unexpected synthesis of three components from the reaction of 4-chloro-3-formylcoumarin with hydroxylamine hydrochloride

Article abstract of DOI:10.13005/ojc/320142

A mild and simple oximation reaction of 4-chloro-3-formylcoumarin with hydroxylamine hydrochloride in basic medium gave unexpected three components via oxime.Those compounds were separatedin good yields by preparative TLC and by chemical means using diffe

Full text of DOI:10.13005/ojc/320142

ISSN: 0970-020 X
CODEN: OJCHEG
2016, Vol. 32, No. (1):
Pg. 379-384
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Unexpected Synthesis of Three Components from
the Reaction of 4-Chloro-3-Formylcoumarin with
Hydroxylamine Hydrochloride
AHMEd ELkHATEEb1,2, ASHwAg S. ALSHEHRI1,
gILbERT kIRSCH3 and SH. H. AbdEL-HAFEz1,4
1Department of Chemistry, Faculty of Science, Taif University, Taif 21974, Saudi Arabia.
2Phytochemistry and Plant Systematic Department,
National Research Centre, Dokki, 12622 Giza, Egypt.
3UMR 7565 SRSMC, Boulevard Arago, 57070 Metz, France.
4Department of Chemistry, Faculty of Science, Assiut University, Assiut71516, Egypt.
*Corresponding author E-mail: shams_abdelhafez@yahoo.com
http://dx.doi.org/10.13005/ojc/320142
(Received: November 03, 2015; Accepted: January 21, 2016)
AbSTRACT
A mild and simple oximation reaction of 4-chloro-3-formylcoumarin with hydroxylamine
hydrochloride in basic medium gave unexpected three components via oxime.Those compounds
were separatedin good yields by preparative TLC and by chemical means using differentreaction
conditions. IR, 1H NMR, 13C NMR and mass spectral data confirmed the structure of the separated
compounds.
key words: 4H-coumarin[3,4-d]isoxazol-4-one; ethyl-5-(2-hydroxyphenyl)-isoxazole-4
-formate; methyl-5-(2-hydroxyphenyl)-isoxazole-4-formate;4-chloro-3-cyano-coumarin.
INTROdUCTION
4-one, and 3-(diaminomethylene) chroman-2,4-dione
were developed3 from the reactions of 3-substituted
chromones (3-formylchromone, 3-formylchromone-
3-oxime, and 3-cyanochromone) with hydroxylamine
inalkalinemedium.3-Formylchromoneswhentreated
with hydroxylamineformed via 3-formylchromone-
oximes 3-cyanochromones4,5.The ability of
3-cyanochromones to interact with water followed
by pyrone ring opening and cyclizationat the CN
group formed 2-amino-3-formylchromone5,6.
Derivatives of 4H-1-benzopyran-4-one, also
known as 4H-chromen-4-ones or chromones, are
an important scaffold in heterocyclic chemistry and
represent useful synthetic building blocks in organic
and medicinal chemistry1.Coumarins or Chromones
are natural products possessing a wide range of
valuable physiological activities2. From literature
survey the syntheses of 2-aminochromone-3-
carboxamide, 3-amino-4H-chromeno[3,4-d]isoxazol-

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ELkHATEEB et al., Orient. J. Chem., Vol. 32(1), 379-384 (2016)
In this study we have investigatedthe isoxazole-4-formate (12b)(depending on the solvent)
reaction of 4-chloro-3-formylcoumarin with formed through oxime(9) (Scheme 1).
hydroxylamine hydrochlorideatdifferent conditions
to see if the reaction will have the same behavior as
previouslydescribed in literature3.
These 3 compounds were prepared as
follow: 1equivalent of starting compound 8 with 1eq.
of hydroxylamine hydrochloride in the presence of
1eq. of sodium acetate as a basic medium were
refluxed for 4 hrs. Formation of compounds 10-
RESULTS ANd dISCUSSION
The literature survey revealed some 12 was monitored by TLC and GC/MS. When the
debate about the assignment of the structure of reaction was carried out by using 3eq hydroxylamine/
the reaction products of coumarin derivatives with 3eq sodium acetate in ethanol and was refluxed
hydroxylamine.
for 10 hrs.purecompound 11was isolated and the
structure confirmed on the basis of IR, HNMR,
1
Among these investigations,Sosnovskikhet 13CNMR and mass spectra.A characteristic singlet
al. in 20083 studied the reactions of chromones peak at ä 10.21 due to CH-isoxazole moiety was
1-3with hydroxylamine hydrochloride in strongly present in HNMR.Treatment of chromones 8(1eq)
1
basic medium to give 3-amino-4H-chromeno[3,4-d] with 3eq of hydroxylamine and 3eq of sodium acetate
isoxazol-4-one 4which was converted into acid 5 under reflux 24hrs.gavepure12 a in ethanol or 12 b
when heated in 10% boiling sodium hydroxide.
in methanol(Scheme 2).
Furtherrecyclization and reduction
Structures of12a and 12b were confirmed
of compound 4led to the formation of on the basis of spectral analysis.Compound
3-(diaminomethylene) chroman-2,4-dione 6.
10was obtained directly when the reaction was
carried out under stirring 5 minutes by using 3eq
Therefore, westudied the reaction of hydroxylamine/3eq sodium acetate in ethanol as a
4-chloro-3-formylcoumarin8 instead of compounds solvent (Scheme 3).
1-3 with hydroxylamine under different conditions.We
identifiedthree unexpected compounds; 4-chloro-3-
It was found that the spectral data of 10were
cyano-coumarin (10); 4H-chromeno[3,4-d]isoxazol- in agreement with literature results [7](m.p.199-
4-one (11); Ethyl-5-(2-hydroxyphenyl)-isoxazole- 200oC). These compounds 10-12 were separated
4-formate (12a); (or methyl-5-(2-hydroxyphenyl)- and purified by chromatographyusinghexane/ethyl
acetate (8:2) as eluent.
Concerning the mechanism10 was formed
O
by elimination of water from oxime (9); 11was formed
by elimination of HCl to ring closure. Finally, the
ethylesterisoxazole12a was obtained via ring opening
of coumarin (lactone)by the action of ethanol.
X
In order to study the effect of solvent, we
have repeated the reaction in methanol instead
of ethanol to give methylesterisoxazole12b
(Scheme2).
O
1-3
X= CHO, CH=NOH, CN
O
NH
2
O
N
OH
O
N
NH2
NH2
NH2
COOH
O
O
O
O
4
5
6

ELkHATEEB et al., Orient. J. Chem., Vol. 32(1), 379-384 (2016)
381
A possible route for the multi-step
Experimental Section
mechanism is outlined in (Scheme 4).
general Procedures.
Melting points were determined by using
the kofler melting point apparatus, and were
uncorrected.IR (kBr, cm-1) spectra were recorded on
a Pye-Unicam SP3–100 instrument atTaif University.
1H NMR spectra were obtained on a Varian (400
MHz) EM 390 USA instrument at king Abdel-Aziz
We suggest that the hydroxylamine
in basic medium converts 8into the key
intermediate compound 9 which then undergoes
further recyclizationby eliminationof HClto afford
coumarino[3,4-d]isoxazole11.Ethanol or methanol
makes the ring opening of the lactone part to form
compounds 12a,b.
13
University. C NMR spectra were recorded on a
JNM-LA spectrometer (100 MHz) at king Abdel-
1
Aziz University, Saudi Arabia. For both H and 13C
In conclusion, the starting compound
4-chloro-3-formyl coumarin 8 showed different
reactivity depending on the reaction conditions.
Its reaction with hydroxylamine gives a variety
of products. The obtained products were 4H-
coumarino[3,4-d]isoxazol-4-one; ethyl-5-(2-
hydroxyphenyl)-isoxazole-4-formate or methyl-
5-(2-hydroxyphenyl)-isoxazole-4-formate) and
4-chloro-3-cyano-coumarin.
–NMR, DMSO d6 was used. Spectra were internally
referenced to TMS. Peaks are reported in ppm
downfield of TMS. Multiplicities are reported as
singlet (s), doublet (d), triplet (t), quartet (q).
MassspectrawererecordedonISQThermo
Scientific GC-MS. GC column TG-SQC, Trace GC
ultra at TaifUniversitykSA.Purity of the compounds
Cl
CN
O
O
10
Cl
Cl
O
N
OH
CHO
POCl3/DMF
a)
NOH
O
O
O
O
O
O
O
O
O
9
11
7
8
OH
N
8
a) 1 eq. of compound , 1 eq. NH2OH, 1 eq. CH3COONa, reflux for 3 hrs in EtOH
COOR
12a
Scheme 1
R=Et
reflux for 10 hrs
11
b)
8
[9]
reflux for 24 hrs
12a,b
R=Et (12a), R=Me (12b)
b) 1 eq. of compound 8, 3 eq. NH2OH, 3 eq. CH3COONa, in EtOH (12a), MeOH (12b)
Scheme 2

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ELkHATEEB et al., Orient. J. Chem., Vol. 32(1), 379-384 (2016)
To a stirred mixture of 4-hydroxycoumarin
was checked by thin layer chromatography (TLC)
using silica gel plates.Column chromatography was 7 (9.72 g, 0.06mol) in anhydrous DMF (46.2 mL,
carried out on 0.04"0.063 mm(Merck) silica gel, thin 0.6 mol) were added dropwise POCl3 (27.6 g, 0.18
layer chromatography was carried out on aluminum mol) at –10° to –5 °C. The reaction mixture was
backed silica plates by Merck and plates were then stirred for 1 hr at room temperature after that
revealed using a UV 254 light.
heated and stirred for 5 hrs.at 80 °C. The reaction
mixture was poured onto crushed ice (300 g) under
vigorous stirring. The reaction mixture was kept
overnight at 0°C.The pale yellow solid was collected
MATERIALS
The 4-hydroxycoumarin 7 was a gift from the Lab of by filtrationand recrystallized from acetone to give
Prof. Gilbert kirsch, Laboratoired’Inge´nierieMole´c 10.5 g (84%) of 8 ; m.p. 133-135°C(lit. 130 °C)9
ulaire et BiochimiePharmacologique, Institut Jean
Barriol, FR Metz, France..
1H-NMR d 10.39 (1H, s, CH=O), 8.16–7.28
(4H, m, Ar-H); IR í 1720 (C=O-pyrone), 1663 (CHO)
cm–1. EI-MS m/z: 208 (M+, 11), 182 (31), 180 (100),
4-Chloro-3-coumarincarbaldehyde (8)
Compound
8 was prepared as 154 (31), 152 (91), 124 (20), 101 (11), 89 (80), 63
previously describe by sabitaeet.al with a little bit (37), 62 (31), 61 (14); EI-HRMS: m/z 207.9909
modification8.
(calculated for C10H5ClO3207.9927)
-H2O
b)
[9]
8
10
5 min stirring
b) 1 eq. of compound 8, 3 eq. NH2OH, 3 eq. CH3COONa, in EtOH
Scheme 3
Cl
Cl
HON
CHO
NH2OH
O
O
O
O
8
9
O
-
H
C
H
H 2
-
C
l
3
C
Cl
O
O
N
a
O
O
N
CN
O
O
10
O
11
ROH
OH
O
N
12a,b
R= Et, Me
COOR
Scheme 4

383
ELkHATEEB et al., Orient. J. Chem., Vol. 32(1), 379-384 (2016)
3-Cyano-4-chlorocoumarin (10), 4H-chromeno ä 165.50, 155.04, 154.90, 152.80, 133.36, 125.29,
[3,4-d]isoxazol-4-one (11), ethyl 5-(2- 124.07, 117.67, 110.24, 107.83. IR í 1761 (C=O-
hydroxyphenyl)isoxazole-4-carboxylate (12a) pyrone), 1608 (C=N) cm–1. EI-MS m/z: 187 (M+,
and Methyl-5-(2-hydroxyphenyl)-isoxazole-4- 100), 159 (33), 131 (11), 119(4), 103 (54), 76 (26).
formate (12b)
EI-HRMS: m/z 187.0268 (calculated for C10H5NO3:
187.0269)
general procedure
To a mixture of NH2OH.HCl (1 eq.) and Ethyl-5-(2-hydroxyphenyl)-isoxazole-4-formate
anhydrous sodium acetate (1 eq.)in ethanol, or (12a)
methanol a solution of compound 8 (1 eq.) in ethanol
m.p.218-220°C;1H-NMR (CDCl3)d 9.02 (1H,
was added. The reaction mixture was refluxed for s, CH-isoxazole), 8.12–7.01 (4H, m, Ar-H), 4.37 (2H,
3hrs. After the reaction completed, the reaction q, J= 6.80 Hz, CH2);1.36 (3H,t, J= 6.80 Hz, CH3).13C-
mixture was poured onto crushed ice (300 g) under NMR ä 175.80, 163.49, 160.60, 155.68, 134.01,
vigorous stirring.The pale yellow solid was collected 125.66, 122.80, 118.68, 116.20.93.54, 60.29, 13.72.
by filtration and further purified by silica gel column IR í 1669 (C=O…H-bond), 1601 (C=N) cm–1. EI-MS
chromatography using a mixture of hexane/ethyl m/z233 (M+, 33), 187 (100), 159 (41), 131 (12),
acetate (8:2) as eluent to afford the desired three 119 (4), 103 (35), 76 (8); EI-HRMS:m/z 233.0684
compounds10, 11 and 12a,b.
(calculated for C12H11NO4: 233.0688)
Notes
Methyl 5-(2-hydroxyphenyl)isoxazole-4-
m.p. 210-212°C;1H-NMR (CDCl3) d 9.02
Compound 10 was prepared by using 3eq carboxylate (12b)
of NH2OH.HCl/ 3eq anhydrous sodium acetate and
1eq of compound 8 in ethanol.The reaction mixture (1H, s, CH-isoxazole), 8.12–7.01 (4H, m, Ar-H),
was stirred for 5 minute to give compound 10 as 3.91 (3H, s, OCH3).IR ν 1670 (C=O…H-bond), 1600
yellow crystal m.p. 198-200°C (Lit, 199-200 °C)9
(C=N) cm–1. EI-MS m/z219 (M+, 49), 187 (100), 159
(34), 131 (15), 119 (4), 103 (99), 76 (40). EI-HRMS:
m/z 219.0492 (calculated for C11H9NO4: 219.0532).
4H-Chromeno [3,4-d]isoxazol-4-one (11)
m.p. 222-224 °C; 1H-NMR d 10.21 (1H, s,
CH-isoxazole), 8.03–7.41 (4H, m, Ar-H); 13C-NMR
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