Thiophosphorylation of pharmacophoric phenols, diols, and triols

Article abstract of DOI:10.1080/10426507.2012.740696

Novel organyldithiophosphonic and bis(aryldithiophosphonic) acids were obtained by the reaction of 2,4-diorganyl 1,3,2,4-dithiadiphosphetane-2,4- disulfides with paracetamol, 4-(1H-pyrrol-1-yl)phenol, ethambutol dihydrochloride, vitamin B₆, and

Full text of DOI:10.1080/10426507.2012.740696

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Phosphorus, Sulfur, and Silicon and the Related
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Thiophosphorylation of Pharmacophoric Phenols, Diols
and Triols
Rafael A. Cherkasov a , Ilyas S. Nizamov a b , Yevgeniy M. Martianov a , Lyubov A. Almetkina a
, Yevgeniy N. Nikitin a & Radik R. Shamilov a
a Kazan Federal University, Kazan, Russia
b State Budgetary-Funded Institution of Science, A. E. Arbuzov Institute of Organic and
Physical Chemistry of Kazan, Scientific Center of Russian Academy of Sciences, Kazan,
Russia
Accepted author version posted online: 01 Nov 2012.
To cite this article: Rafael A. Cherkasov, Ilyas S. Nizamov, Yevgeniy M. Martianov, Lyubov A. Almetkina, Yevgeniy N. Nikitin &
Radik R. Shamilov (2012): Thiophosphorylation of Pharmacophoric Phenols, Diols and Triols, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI:10.1080/10426507.2012.740696
To link to this article: http://dx.doi.org/10.1080/10426507.2012.740696
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ACCEPTED MANUSCRIPT
THIOPHOSPHORYLATION OF PHARMACOPHORIC PHENOLS, DIOLS AND
TRIOLS
Rafael A. Cherkasov,1 Ilyas S. Nizamov,1, 2 Yevgeniy M. Martianov,1 Lyubov A. Almetkina,1
Yevgeniy N. Nikitin,1 and Radik R. Shamilov1
1Kazan Federal University, Kazan, Russia
2State Budgetary-Funded Institution of Science, A. E. Arbuzov Institute of Organic and Physical
Chemistry of Kazan, Scientific Center of Russian Academy of Sciences, Kazan, Russia
Address correspondence to: Ilyas S. Nizamov, Kazan Federal University, Kremlievskaya, 18,
Kazan 420008, Russia. Email: isnizamov@mail.ru
Keywords: 1,3,2,4-Dithiadiphosphetane-2,4-disulfides; paracetamol; 4-(1H-pyrrol-1-yl)phenol;
ethambutol; vitamin B6
Abstract: Novel organyldithiophosphonic and bis(aryldithiophosphonic) acids were obtained by
the reaction of 2,4-diorganyl 1,3,2,4-dithiadiphosphetane-2,4-disulfides with paracetamol, 4-
(1H-pyrrol-1-yl)phenol, ethambutol dihydrochloride, vitamin B6 and its acetonide derivatives.
INTRODUCTION
1
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Tetracoordinated organophosphorus thioacids as well as their derivatives are useful to
develop convenient methods for preparing new types of drugs and pesticides. Compounds
containing stereogenic centers at the phosphorus atom seem to possess appreciable biological
activity. To obtain biological active dithiophosphonic and bis(dithiophosphonic) acids we have
used substituted phenols, diols and triols bearing pharmacophoric functionalities in the organic
framework in the reaction with Lawesson-like reagents.
RESULTS AND DISCUSSION
Paracetamol, which is widely used as analgetic and antipyretic agent, reacts with 2,4-
diaryl 1,3,2,4-dithiadiphosphetane-2,4-disulfides at 20 – 40 °C during 1-2 h in C6H6/CHCl3
suspension with formation of the corresponding aryldithiophosphonic acids. The similar result
was obtained in the case of 2,4-diferrocenyl 1,3,2,4-dithiadiphosphetane-2,4-disulfide (Scheme
1). The 31P NMR spectra of the thioacids obtained in benzene solutions show singlets in the
range of Р = 79 – 89 ppm.
S
P
O
O
S
R
S
S
R
S
H
N
H
R
P
P
+
2
HO
2
O
N
Me
HS
Me
tBu
R = HO
tBu
,
,
Ferrocenyl
O
2
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Scheme 1
Thiophosphorylation of 4-(1H-pyrrol-1-yl)phenol by 2,4-diorganyl 1,3,2,4-dithiadiphos-
phetane-2,4-disulfides at 20 °C during 1 h in benzene (Scheme 2) yields new corresponding
dithiophosphonic acids (Р = 90 ppm). These acids were transformed into the respective
ammonium salts (Р = 113 ppm).
HO
N
2
S
P
S
P
R
S
S
R
S
S
NH3
R
R
P
P
2
O
N
O
N
HS
S
NH4
tBu
HO
,
,
Ferrocenyl
R =
O
tBu
Scheme 2
The bis(organyldithiophosphonic) acids (Р = 93 – 97 ppm) were prepared by the reaction
of 2,4-diorganyl 1,3,2,4-dithiadiphosphetane-2,4-disulfides with ethambutol dihydrochloride
(Scheme 3) usually used as an antimicrobacterial agent (20 °C, 12 h, C6H6/CHCl3).
3
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SH
R
S
P
O
OH
Cl
Cl
H2
N
H2
N
S
R
S
S
R
S
P
P
+
N
H2
N
H2
Cl
O
P
HO
Cl
R
S
HS
tBu
HO
,
,
Ferrocenyl
R =
O
tBu
Scheme 3
A tris(aryldithiophosphonic) acid (Р = 93 ppm) was isolated from the reaction of vitamin
B6 hydrochloride with an 2,4-diaryl 1,3,2,4-dithiadiphosphetane-2,4-disulfide at 80 °C during 2 h
in benzene. Two acetonide derivatives of vitamin B6 react with a 2,4-diaryl 1,3,2,4-dithiadiphos-
phetane-2,4-disulfide (20 – 30 °C, 1 h, C6H6/CHCl3) to form inner ammonium salts of the
corresponding aryldithiophosphonic acids.
4
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Me
Me
Me
Me
O
O
Me
OH
O
S
Me
Me
Me
O
HO
Me
Ar
O
O
P
2
S
2
O
S
O
N
S
S
S
Ar
S
P
O
Me
N
O
Ar
2
P
P
S
2
Ar
Me
N
H
Me
N
H
OH
HO
Me
OH
N
Cl
H
S
S
Ar
SH
Ar
HS
O
P
tBu
Ar = HO
tBu
P
S
O
Ar
SH
P
O
Me
N
H
Cl
Scheme 4
The organyldithiophosphonic and bis(aryldithiophosphonic) acids prepared possess
appreciable antimicrobial activity.
ACKNOWLEDGEMENT
The study was performed with financial support of the Russian Foundation for Basic Researches
(Grant No. 11-03-00264-a).
5
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