Phosphorylation and amine-induced dephosphorylation of 4-chlorocoumarin-3- carboxaldehyde and 4-chloro-3-(β,β-dicyanoethenylidene)coumarin

Article abstract of DOI:10.1080/713744562

4-Chlorocoumarin-3-carboxaldehyde (1) and 4-chloro-3-(β,β- dicyanoethenylidene)coumarin (2) produce their respective 1:1 phosphonate adducts (5a-c) and (6a-c) upon reaction with the appropriate dialkylphosphonates (3a-c). Compounds 5 undergo dechlorination and dephosphorylation upon reaction with certain primary aliphatic amines to yield 9 (or 10) according to the nature of the amine used. Compounds 1 and 2 undergo dechlorination through reaction with hexamethyl-phosphorustriamide 4 to give the respective 4-dimethylamino-derivatives (11a and 11b). Structural reasonings for the new compounds are based on compatible analytical and spectroscopic measurements. The mechanism for formation of compounds 11 also is discussed.

Full text of DOI:10.1080/713744562

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Phosphorus, Sulfur, and Silicon and the Related
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Phosphorylation and Amine-induced Dephosphorylation
of 4-Chlorocoumarin-3-carboxaldehyde and 4-Chloro-3-
(β,β-dicyanoethenylidene)coumarin
Maha Darwish Khidre a
a National Research Centre, Dokki, Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: Maha Darwish Khidre (2003) Phosphorylation and Amine-induced Dephosphorylation of 4-
Chlorocoumarin-3-carboxaldehyde and 4-Chloro-3-(β,β-dicyanoethenylidene)coumarin, Phosphorus, Sulfur, and Silicon and the
Related Elements, 178:10, 2147-2158, DOI: 10.1080/713744562
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Phosphorus, Sulfur, and Silicon, 178:2147–2158, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390228602
PHOSPHORYLATION AND AMINE-INDUCED
DEPHOSPHORYLATION OF
4-CHLOROCOUMARIN-3-CARBOXALDEHYDE AND 4-
CHLORO-3-(β, β-DICYANOETHENYLIDENE)COUMARIN
Maha Darwish Khidre
National Research Centre, Dokki, Cairo, Egypt
(Received December 7, 2002; accepted April 24, 2003)
4-Chlorocoumarin-3-carboxaldehyde (1) and 4-chloro-3-(β,β-dicy-
anoethenylidene)coumarin (2) produce their respective 1:1 phospho-
nate adducts (5a–c) and (6a–c) upon reaction with the appropri-
ate dialkylphosphonates (3a–c). Compounds 5 undergo dechlorination
and dephosphorylation upon reaction with certain primary aliphatic
amines to yield 9 (or 10) according to the nature of the amine
used. Compounds 1 and 2 undergo dechlorination through reac-
tion with hexamethyl-phosphorustriamide 4 to give the respective 4-
dimethylamino-derivatives (11a and 11b). Structural reasonings for
the new compounds are based on compatible analytical and spectro-
scopic measurements. The mechanism for formation of compounds 11
also is discussed.
Keywords: Amine-induced dephosphorylation; coumarins; di-
alkylphosphonates; hexamethylphosphorustriamide; phosphonates;
reaction mechanism
It is widely realized that the activity of certain natural products,
drugs and pesticides owes much to presence of a coumarin nucleus
in their molecules.1,2 Various widely used oral anticoagulants and
rodenticides3 also incorporate the same nucleus. Therefore, it appeared
of interest to study the reaction of 4-chloro coumarin-3-carboxaldehyde
(1) and 4-chloro-3-(β,β-dicyanoethenylidene)coumarin (2) with dialkyl-
phosphites (3a–c) and hexamethylphosphorustriamide (4). Compound
2 is now prepared for the first time by reacting 1 with malononitrile in
ethanol. Phosphorylation of compounds 1 and 2 may endow interesting
Address correspondence to Maha Darwish Khidre, Department of Pesticide Chem-
istry, National Research Centre, Dokki, Cairo, Egypt. E-mail: mdkhedr@yahoo.com
2147

2148
M. D. Khidre
biocidal potentialities to the new products. The present study runs thus
in the line with our growing interest that searchs for new organophos-
phorus compounds derived from heterocycles4−6 for evaluating their
biological activities.
RESULTS AND DISCUSSION
It has been now found that 4-chlorocoumarin-3-carboxaldehyde (1)∗
reacts with dialkyl phosphites (3a–c) at 100◦C in absence of solvent to
give colorless phosphonate 1:1 adducts for which structures 5a–c are
respectively assigned.
Structural reasoning for 5 are: Compatible elementary and molecu-
lar weight determinations (MS) were gained for 5a–c. Positive chemi-
cal shifts were recorded for 5a (δ = 20.80 ppm) [31P-NMR spectrum (vs
85% H3PO4], confirming the presence of phosphorus-to-carbon linkage
(phosphonate group).7
The IR spectrum (KBr, cm−1
)
of 4-chloro-3-[(α-dimethoxy-
phosphoryl-α-hydroxy)methyl]coumarin (5a), taken as a representative
example, showed absorption bands at 3250 (OH), 1685 (C O, lactone),
1520 (C C, aromatic), 1220 (P O)8, 1050 (P O CH3)8 and at 860
( C Cl). The latter band appeared in the IR spectrum of 1 at 780.
1
The H NMR spectrum of 5a (CDCl3, δ ppm) showed protons of the
OCH3 groups attached to phosphorus as two doublets (each with 3JHP
12 Hz) at 3.95 and 3.75. Apparently, the asymmetry of the molecule
=
∗Also known as 4-chloro-3-formylcoumarin and 4-chloro-2-oxo-2H-chromene-3-
carbaldehyde.

Phosphorylation and Amine-Induced Dephosphorylation
2149
due to the presence of a stereo-center would render the two methoxyl
groups diastereotropic and hence anisochronous; resulting thus in the
observed splitting pattern.9 The spectrum revealed the P-CH proton as
a doublet (2JHP = 22 Hz) at 5.50. The spectrum also showed a multiplet
in the region 8.00–7.40 (4H, aromatics) and a broad singlet at 4.25 (OH,
exchangeable with D2O).
The mass spectrum of 5a showed the molecular ion peak at m/z 318
.
(320) which corresponded to C12H12ClO6P. Loss of P(O)(OCH3)2 radi-
cal from M+ afforded the base peak (cation a) at m/z 209 (211). Mean-
while, loss of H(O)P(OCH3)2 molecule from M+ afforded cation b at
m/z 208 (210) which corresponded to the molecular ion peak of com-
pound 1 itself [MS: m/z 208 (210), C10H5ClO3]. This behavior of 5a un-
der electron impact recalls its thermolysis upon heating under reduced
pressure which yields compound 1 and dimethyl phosphite 3a (see
Experimental).
The 13C-NMR of 5a showed signals at 53.69 (C OH), 67.24 (OCH3),
68.54 (OCH3), 116.88, 118.16, 120.97, 125.43, 126.28, 133.47, 151.70,
159.96, coumarin ring carbon atoms and at 211.40 (C O).
In the same sense, 4-chloro-3-(β,β-dicyanoethenylidene)coumarin
(2) reacted with dialkylphosphonates (3a–c) to give colorless phos-
phonate 1:1 adducts for which structure 6a–c were assigned
respectively.

2150
M. D. Khidre
Compatible elementary and molecular weight determinations (MS)
were gained for all adducts. They showed positive chemical shifts in
the region 15–20 ppm (vs. H3PO4) in their 31P NMR spectra; indicating
that they are phosphonate in nature.7
The IR spectrum (KBr, cm−1) of 6a taken as example, revealed the
presence of absorption bands at 2220 (CN), 1260 (P O, free), 1050
(P O CH3) and 765 (C Cl). The latter band appeared in the spectrum
of 2 at 760 cm−1
.
1
The H NMR spectrum of 6a (CDCl3, δ ppm) showed protons of the
two methoxyl groups attached to phosphorus (6H) as two doublets (each
with 3JHP = 12 Hz) at 3.95 and 3.80. The exocyclic methine protons (2H)
appeared in doublet patterns. That of the CH P group appeared at 4.50
(2d, 2JHP = 18 Hz) while that of the P C CH grouping appeared at 5.2
3
(2d, JHP = 12 Hz). The multiplet (4H) due to the aromatic protons
appeared in the region 8.00–7.35 ppm. Presence of an AB-system due
to protons of the P CH CH-grouping and lack of a signal due to protons
of a methylene group ( CH2 C P) rules out an alternative structure
like 7.
The mass spectrum of 6a showed the molecular ion peak at m/z 366
(368); corresponding to C15H12ClN2O5P. Loss of CH(CN)2 radical from
M+ yields cation c at m/z 301 (303). Meanwhile, loss of Cl radical from
M+ affords cation d at m/z 331 (base peak). The molecular ion peak of
6a can also eject a neutral HCl molecule to give a radical cation of type e
(m/z 330). Cation g at m/z 257 is most probably formed via expulsion of
P(O)(OCH3)2 radical from M+. The same process also can afford cations
h, m/z 109 and i, m/z 110 respectively.

Phosphorylation and Amine-Induced Dephosphorylation
2151
Compounds 6 regenerate the appropriate starting materials (2 +
3) upon thermolysis under reduced pressure. 13C NMR spectrum
of 6a showed signals at 39.98 ( CH), 42.30 ( CH), 53.68 (OCH3),
55.11 (OCH3), 110.76, 111.29, 117.70 (125.65), 126.81, 134.20, 152.11,
158.85 coumarin ring carbon atoms, 117.07, 117.94 (CN)2 and 201
(C O).
In an attempt to obtain new structures incorporating both P and N
moieties as in the case of a variety of broadly used biocides,10−12 we
have investigated the reaction of certain amines with compounds 5.
The beseeched products 8, however, could not be formed. Instead, com-
pounds 5 underwent amine-induced dephosphorylation yielding ami-
nated products of type 9.

2152
M. D. Khidre
The Schiff base 10 was formed only when ethylamine was used in
the transamination reaction. Compatible elementary and spectroscopic
data were obtained for compounds 9a–c and 10. Elementary analyses
and molecular weight determination (MS) of 9c, taken as a representa-
tive example, corresponded to C13H13NO4. Its IR spectrum (KBr, cm−1
)
showed bands at 3400 (NH), 1680 (C O), 1610, 1550 (C C) and 1260
1
(C O, stretching). The H NMR of 9c (CDCl3, δ ppm) showed signals
at 12.15 (NH, s), 8.05–7.30 (4H, aromatics, m), 10.20 (C CH, s), 4.10
(CH2, d, JHH = 9 Hz), 3.80 (CH2, d, JHH = 9 Hz), 3.50 (3H, OCH3, s),
and 3.35 (2H, CH2, d, JHH = 9 Hz). Its 13CNMR spectrum showed sig-
nals due to the C O groups at 211.82 (C O, pyrone) and at 191.84
ppm (C O, aldehyde). The coumarin-ring carbon atoms appeared as
a cascade of signals at 106.76, 114.12, 118.89, 123.63, 127.37, 134.45,
155.46, and 159.73 ppm. The spectrum also showed signals at 70.40
(CH2), 59.40 (OCH3), 47.52 (CH2). This conclusion is also confirmed
by Distortion less Enhancement by Polarization Transfer (DEPT)
measurement
The behavior of compounds 1 and 2 toward hexamethylphosphorus-
triamide 4 also was investigated. The reactions proceeded in tetrahy-
drofuran at ambient temperature to give products devoid of phosphorus
(11a and 11b respectively).
Compounds 11a and 11b were unequivocally prepared and identified
(m.p., mixed m.p. and comparative IR and MS spectra) upon reacting 1
and 2, respectively with dimethylamine in tetrahydrofuran.
The reaction mechanism is depicted in Scheme 1. Initial nucleophilic
attack by the phosphine-phosphorus atom on 1 (or 2) would produce a
betaine of structure like 12.13b By virtue of the great affinity of phos-
phonium ions to halides,13a would facilitate formation of a transient
betaine of type 13. The latter in which phosphorus can act as a good
leaving group due to its bulkiness13a decomposes then to afford 11.
Analytic and spectroscopic data recorded for compound 11 afford
strong support for the postulated mechanism.

Phosphorylation and Amine-Induced Dephosphorylation
2153
SCHEME 1
CONCLUSION
Apparently, 4-chloro-3-coumarincarboxaldehyde (1) and 4-chloro-(β,β-
dicyanoethenylidene)coumarin (2) undergo preferential attack by di-
alkylphosphonates (3a–c) at position-3 to give phosphonate 1:1 adducts
of types 5 and 6 respectively. Adducts 5 undergo amine-induced dephos-
phorylation and dechlorination upon reaction with aliphatic primary
amines. In terms of the Hard-Soft-Acid-Base (HSAB) principle,14,15 the
reacting amines may be considered as softer (stronger) bases, than di-
alkyl phosphonates (3).
Hexamethylphosphorustriamide 4 induces chlorine displacement in
1 and 2 to yield the respective 4-(dimethylamino)- derivatives 11. To
the best of our knowledge, this represents a new era for utilising 4 as
an aminating agent.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded in
KBr using UNICAM SP 1100 or PU 7912 Infracords. The 1H NMR
spectra were recorded on Jeol GLMEX 270 MHz Spectrometer (Super
conducting magnet) in CDCl3 using TMS as an internal standard, 31P-
NMR spectra were recorded with Jeol GLMEX 270 MHz Spectrometer
in CDCl3 (vs. 85% H3PO4). The mass spectra were obtained with Finni-
gan MAT-SSQ 7000 Spectrometer at 70 eV.

2154
M. D. Khidre
4-Chloro-2-oxo-2H-chromene-3-carboxaldehyde was prepared by a
known procedure.17 The phosphorus reagents and amines were avail-
able from Aldrich Co. The phosphites were freshly distilled before use.
Physical and spectral data of the new compounds are compiled in
Tables I and II.
Preparation of 4-Chloro-3-(β, β-dicyanoethenylidene)-
coumarin (2)
A mixture of 1 (2.08 g, 0.01 mmol) and malononitrile (0.66 g, 0.01 mmol)
in 50 ml absolute ethanol was stirred at room temperature for 4 h.
The solid formed was collected then recrystallized from cyclohexane to
give 2 as yellow crystals, yield 79%. Physical and analytical data of
1
compound 2 are presented in Table I. The H NMR spectrum showed
a multiplet due to the aromatic protons in the δ 8.00–7.30 region
wherein emerged a singlet (1H) at δ 7.80 due to the exocyclic ethylenic
proton.
Reaction of 4-Chlorocoumarin-3-carboxaldehyde (1) and
4-chloro-3-(β, β-dicyanoethenylidene)coumarin (2) with
Dialkyl Phosphites (3a–c)
General Procedure
A mixture of 1 (0.01 mmol) and dialkyl phosphite (dimethyl-, diethyl-,
and diisopropyl phosphites, 5 ml) was heated in the absence of solvent
at 100◦C for 2–4 h. After removing the volatile materials in vacuo, the
residue was triturated with light petroleum and left to cool. The solid
so formed was collected and recrystallized from a suitable solvent to
give compounds 5a–c.
Similarly compounds 6a–c were isolated upon reacting 2 with 3a–c
(yield 80%). Physical, analytical and spectral data for compounds 5a–c
and 6a–c are presented in Tables I and II.
Action of Heat on Phosphonate 5a
Compound 5a (0.05 g) was heated in a cold finger sublimator at 230◦C
(bath temperature) under reduced pressure (5 mm/Hg) for 30 min.
The compound that sublimed was collected (85%), recrystallized from
ethyl alcohol to give yellow crystals, proved to be 4-chlorocoumarin-3-
carboxaldehyde (1) (m.p., mixed m.ps. 123◦C, and comparative IR spec-
tra). Dimethyl phosphite was detected in receiver by the development
of a violet color on addition of 3,5-dinitrobenzoic acid in the presence of
alkali.16

2155

2156

Phosphorylation and Amine-Induced Dephosphorylation
2157
Reaction of Phosphonate 5a with Amines
General Procedure
A solution of the amine (propylamine, butylamine methoxy-ethyl
amine) (2 mmol) in absolute methanol (20 ml) was added dropwise
at 0–5◦C to a stirred mixture of 5a (1 mmol) in the same solvent
over a period of 30 min. Upon cooling for 2 h, the crystalline product
which separated was collected by filtration, washed successively with
methanol, and water then recrystallized from a suitable solvent to give
compounds 9a–c. After concentrating the filtrates under reduced pres-
sure additional products were obtained; for more details see Tables I
and II.
Reaction of Phosphonate 5a with Ethylamine
A solution of ethylamine (2 mmol) in absolute ethanol (20 ml) was added
dropwise at 0–5◦C to a stirred mixture of 5a (1 mmol) in the same sol-
vent (5 ml) over a period of 10 min. On cooling, the crystalline prod-
uct which separated was collected by filtration, washed successively
with ethanol and water, then recrystallized from cyclohexane. (Tables I
and II).
Reaction of 1 and 2 with Hexamethylphosphorustriamide
(HMPT) (4)
General Procedure
A mixture of 1 (2.08 g, 0.01 mmol) and HMPT (0.01 mmol) in dry
tetrahydrofuran (50 ml) was kept at room temperature for 2 h and
the solid formed was collected, then recrystallized from petroleum
ether (40–60◦C)/ether to give 11a (yield: 75%). Similarly 11b was
isolated upon reacting 2 with 4 (yield 85%). Physical, analytical
and spectral data of compounds 11a,b are presented in Tables I
and II.
Reaction of 1 and 2 with Dimethylamine
General Procedure
A mixture of 1 (0.01 mmol) and dimethylamine (0.01 mmol) in dry
tetrahydrofuran (50 ml) was refluxed for 4–6 h and the solid formed
was collected and proved to be 11a (m.p., mixed m.p. and compara-
tive IR and MS spectra). Similarly 11b was isolated upon reacting
2 (0.01 mmol) and diethylamine (0.01 mmol) in dry tetrahydrofuran
(50 ml).

2158
M. D. Khidre
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