Simple and efficient synthesis of new O,O-diethyl phosphorothioates

Article abstract of DOI:10.1134/S1070428009030142

A simple and highly effective method was developed for the synthesis of new O,O-diethyl phosphorothioates from O,O-diethyl phosphorochloridothioate and 2-chloroquinolin-3-ylmethanol derivatives in the presence of sodium hydroxide.

Full text of DOI:10.1134/S1070428009030142

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 430–433. © Pleiades Publishing, Ltd., 2009.
Published in Russian in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 3, pp. 440–443.
Simple and Efficient Synthesis of New
O,O-Diethyl Phosphorothioates*
R. U. Pokalwar, R. V. Hangarge, A. H. Kategaonkar, and M. S. Shingare
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, 431004 (M.H.) India
fax: +912402400491; e-mail: msshingare11@rediffmail.com
Received November 16, 2007
Abstract—A simple and highly effective method was developed for the synthesis of new O,O-diethyl phos-
phorothioates from O,O-diethyl phosphorochloridothioate and 2-chloroquinolin-3-ylmethanol derivatives in the
presence of sodium hydroxide.
DOI: 10.1134/S1070428009030142
Quinolines [1] constitute an important class of het-
erocyclic compounds which exhibit versatile biological
activity, including bactericidal [2], antitumor [3], anti-
inflammatory [4], and antimalarial [5]. Such quinolines
as 2-chloroquinoline-3-carbaldehyde occupy a promi-
nent position as key intermediates for further annela-
tion and various modifications of functional groups
[6]. Organic phosphates are potent pesticides which
have a variety of applications [7]. Recently, some new
vinyl phosphates have been reported as potent inhibi-
tors of phosphatase [8] and phosphodiesterase [9].
There are only a few reports on the synthesis and bio-
logical activity of their analogs possessing insecticidal
[10] and antifungal [11] activity. Phosphonates [12]
and α-aminophosphonates are important biologically
active compounds [13] due to their structural analogy
to amino acids, and they have become the subject of
considerable interest. They act as peptide mimics [14],
enzyme inhibitors [15], antibiotics, and pharmacolog-
ical agents [16]. Phosphorothioates have found a wide
range of applications in industrial, agricultural, and
medicinal chemistry due to their biological and physi-
cal properties, as well as synthetic intermediates [17].
Phosphorothioate-based pesticides and analogs of bio-
logically active phosphoric diesters were prepared
[18]. In the recent years, a number of phosphorothio-
ates have been proposed as potential chemotherapeu-
tic agents [19] and inhibitors of some enzymes [20].
Phosphorothioates are commonly synthesized by
reaction of dialkyl phosphites with sulfenyl chlorides
[21], sulfenyl cyanides [22], thiosulfonates [23], disul-
fides [24], and sulfur [25], as well as by condensation
of phosphorochloridates with thiols [26]. All these
methods suffer from some disadvantages, including
drastic reaction conditions and severe side reactions.
In continuation of our work related to phosphorus
chemistry [27], we were interested in the synthesis of
new O,O-diethyl phosphorothioates. In the present
article we report on a two-step synthesis of new
O,O-diethyl phosphorothioates containing highly bio-
active quinoline moiety. In the first step, 2-chloroquin-
olin-3-ylmethanol derivatives IIa–IIh were synthe-
Scheme 1.
S
P
R1
R2
CHO
Cl
R1
R2
CH2OH
Cl
R1
R2
(EtO)2P(S)Cl
Me2CO, NaOH
OEt
OEt
NaBH4, MeOH
O
N
N
N
Cl
R3
R3
R3
Ia–Ih
IIa–IIh
IIIa–IIIh
I–III, R1 = R2 = R3 = H (a); R1 = Me, R2 = R3 = H (b); R1 = R3 = H, R2 = Me (c); R1 = R2 = H, R3 = Me (d); R1 = MeO, R2 = R3 =
H (e); R1 = R3 = H, R2 = MeO (f); R1 = R2 = H, R3 = Et (g); R1 = EtO, R2 = R3 = H (h).
* The text was submitted by the authors in English.
430

SIMPLE AND EFFICIENT SYNTHESIS OF NEW O,O-DIETHYL PHOSPHOROTHIOATES
431
sized by reduction of the corresponding substituted
2-chloroquinoline-3-carbaldehydes Ia–Ih with sodium
tetrahydridoborate in methanol at room temperature,
and in the second step compounds IIa–IIh were con-
verted into O,O-diethyl O-(2-chloroquinolin-3-yl)-
methyl phosphorothioates IIIa–IIIh by treatment with
O,O-diethyl phosphorochloridothioate in acetone in the
presence of sodium hydroxide (Scheme 1). Phos-
phorothioates IIIa–IIIh were isolated in almost quan-
titative yield and were characterized by elemental anal-
yses and IR, 1H NMR, and mass spectra.
Compounds IIa and IIc–IIh were synthesized in
a similar way. Listed below are comp. no., yield (%),
and melting point, °C: IIa, 95, 166–168; IIc, 96, 131–
133; IId, 94, 160–162; IIe, 97, 129–131; IIf, 95, 122–
124; IIg, 97, 120–122; IIh, 94, 130–132.
O-(2-Chloro-6-methylquinolin-3-yl)methyl
O,O-diethyl phosphorothioate (IIIb). O,O-Diethyl
phosphorochloridothioate, 1.5 g (7.9 mmol), was
added under stirring to a solution of 1.0 g (4.8 mmol)
of 2-chloro-6-methylquinolin-3-ylmethanol and 0.5 g
(12.5 mmol) of sodium hydroxide in 10 ml of acetone,
and the mixture was stirred until the reaction was com-
plete (20 min; TLC, hexane–ethyl acetate, 8:2). The
mixture was poured on crushed ice, and the precipitate
was filtered off, washed with water, and dried in
a vacuum oven at 40°C for 6.0 h. Yield 1.70 g
(98.3%), mp 71–73°C. IR spectrum, ν, cm–1: 2989
Thus the proposed procedure ensures synthesis of
new O,O-diethyl phosphorothioates from (2-chloro-
quinolin-3-yl)methanol derivatives using O,O-diethyl
phosphorochloridothioate in the presence of sodium
hydroxide under mild conditions in a short time and
with almost quantitative yields. It may be useful for
combinatorial chemistry.
1
(C–H), 1242 (P=S), 1021 (P–O–C). H NMR spec-
trum, δ, ppm: 1.31–1.40 t (6H, CH2CH3, J = 8 Hz),
2.53 s (3H, 6-CH3), 4.14–4.22 m (4H, OCH2CH3),
5.27 d (2H, 3-CH2, J = 9 Hz), 7.56 d (1H, 7-H, J =
8 Hz), 7.61 s (1H, 5-H, J = 8 Hz), 7.92 d (1H, 8-H, J =
8 Hz), 8.20 s (1H, 4-H). Mass spectrum, m/z: 360.1
[M + 1]+, 362.1 [M + 3]+. Found, %: C 50.12; H 5.45;
N 3.75. C15H19ClNO3PS. Calculated, %: C 50.07;
H 5.32; N 3.89.
EXPERIMENTAL
2-Chloroquinoline-3-carbaldehydes Ia–Ih were pre-
pared according to the procedure described previously
[28] and were purified by column chromatography
over silica gel (60–120 mesh). O,O-Diethyl phospho-
rochloridothioate was commercial product (Lancaster).
Acetone, sodium tetrahydridoborate, sodium hydrox-
ide, and methanol were purchased from S.D. Fine-
Chem. All melting points were determined in open
capillaries on Kumar’s melting point apparatus. The
1H NMR spectra were recorded on a Varian Mercury
Plus spectrometer (400 MHz) from solutions in CDCl3
using TMS as internal standard. The IR spectra were
measured in KBr on a Perkin-Elmer FTIR instrument.
The mass spectra were obtained on a Micromass
Quattro II mass spectrometer (electrospray ionization).
The purity of products and the progress of reactions
were monitored by TLC on Merck silica gel plates.
Compounds IIIa and IIIc–IIIh were synthesized in
a similar way.
O-(2-Chloroquinolin-3-yl)methyl O,O-diethyl
phosphorothioate (IIIa). Reaction time 25 min. Yield
95%, mp 52–54°C. IR spectrum, ν, cm–1: 2992 (C–H),
1
1234 (P=S), 1032 (P–O–C). H NMR spectrum, δ,
ppm: 1.31–1.35 t (6H, CH2CH3, J = 8 Hz), 4.14–
4.22 m (4H, OCH2CH3), 5.29 d (2H, 3-CH2, J = 8 Hz),
7.56 t (1H, 6-H, J = 8 Hz), 7.72 t (1H, 7-H, J = 8 Hz),
7.84 d (1H, 5-H, J = 8 Hz), 8.00 d (1H, 8-H, J = 8 Hz),
8.28 s (1H, 4-H). Mass spectrum, m/z: 346.0 [M + 1]+,
348.0 [M + 3]+. Found, %: C 48.72; H 4.98; N 4.15.
C14H17ClNO3PS. Calculated, %: C 48.63; H 4.96;
N 4.05.
2-Chloro-6-methylquinolin-3-ylmethanol (IIb).
Sodium tetrahydridoborate, 0.2 g (5.2 mmol) was
slowly added under stirring at room temperature to
a solution of 1.5 g (7.2 mmol) of 2-chloro-6-methyl-
quinoline-3-carbaldehyde (Ib) in 10 ml of methanol.
The progress of the reaction was monitored by TLC
using hexane–ethyl acetate as eluent. When the reac-
tion was complete (10 min), the mixture was concen-
trated under reduced pressure, the residue was treated
with ice water, and the precipitate was filtered off,
washed with water, and dried in an oven at 50°C for
8.0 h. Yield 1.44 g (95.4%), mp 144–146°C. Mass
spectrum, m/z: 207.8 [M + 1]+, 209.9 [M + 3]+.
O-(2-Chloro-7-methylquinolin-3-yl)methyl
O,O-diethyl phosphorothioate (IIIc). Reaction time
25 min. Yield 96%, mp 53–55°C. IR spectrum, ν, cm–1:
1
2981 (C–H), 1231 (P=S), 1028 (P–O–C). H NMR
spectrum, δ, ppm: 1.30–1.34 t (6H, CH2CH3, J =
8 Hz), 2.55 s (3H, 7-CH3), 4.13–4.20 m (4H, OCH2-
CH3), 5.27 d (2H, 3-CH2, J = 8 Hz), 7.39 d (1H, 6-H,
J = 8 Hz), 7.72 d (1H, 5-H, J = 8 Hz), 7.78 s (1H,
8-H), 8.22 s (1H, 4-H). Mass spectrum, m/z: 360.1
[M + 1]+, 362.0 [M + 3]+. Found, %: C 50.18; H 5.35;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

POKALWAR et al.
432
N 3.84. C15H19ClNO3PS. Calculated, %: C 50.07;
H 5.32; N 3.89.
O-(2-Chloro-6-ethoxyquinolin-3-yl)methyl
O,O-diethyl phosphorothioate (IIIh). Reaction time
25 min. Yield 98%, mp 76–78°C. IR spectrum, ν, cm–1:
O-(2-Chloro-8-methylquinolin-3-yl)methyl
O,O-diethyl phosphorothioate (IIId). Reaction time
25 min. Yield 97%, bp 164–166°C (760 mm). IR spec-
trum, ν, cm–1: 2986 (C–H), 1223 (P=S), 1027 (P–O–C).
1H NMR spectrum, δ, ppm: 1.31–1.39 t (6H, OCH2-
CH3, J = 8 Hz), 2.74 s (3H, 8-CH3), 4.13–4.21 m (4H,
OCH2CH3), 5.27 d (2H, 3-CH2, J = 8 Hz), 7.42 t (1H,
6-H, J = 8 Hz), 7.55 d (1H, 7-H, J = 8 Hz), 7.64 d (1H,
5-H, J = 8 Hz), 8.22 s (1H, 4-H). Mass spectrum, m/z:
360.1 [M + 1]+, 362.1 [M + 3]+. Found, %: C 50.01;
H 5.235; N 3.98. C15H19ClNO3PS. Calculated, %:
C 50.07; H 5.32; N 3.89.
1
2989 (C–H), 1227 (P=S), 1020 (P–O–C). H NMR
spectrum, δ, ppm: 1.31–1.34 t (6H, OCH2CH3, J =
8 Hz), 1.46 t (3H, 6-OCH2CH3, J = 8 Hz), 4.11–4.21 m
(6H, OCH2CH3), 5.26 d (2H, 3-CH2, J = 8 Hz), 7.07 d
(1H, 5-H, J = 4 Hz), 7.35 d.d (1H, 7-H, J = 4, 4 Hz),
7.88 d (1H, 8-H, J = 8 Hz), 8.15 s (1H, 4-H). Mass
spectrum, m/z: 390.1 [M + 1]+, 392.1 [M + 3]+. Found,
%: C 49.42; H 5.32; N 3.69. C16H21ClNO4PS. Calcu-
lated, %: C 49.30; H 5.43; N 3.59.
The authors thank the Head of the Department of
Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, for providing laboratory
facilities.
O-(2-Chloro-6-methoxyquinolin-3-yl)methyl
O,O-diethyl phosphorothioate (IIIe). Reaction time
20 min. Yield 97%, mp 82–84°C. IR spectrum, ν, cm–1:
1
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2983 (C–H), 1228 (P=S), 1022 (P–O–C). H NMR
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