Synthesis of 1,3,4-thiazaphosphols containing aminocarboxylic acid fragments in the molecule

Full text of DOI:10.1134/S1070363209080283

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 8, pp. 1748–1749. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © M.A. Pudovik, R.Kh. Bagautdinova, D.A. Pudovik, 2009, published in Zhurnal Obshchei Khimii, 2009, Vol. 79, No. 8, pp. 1390–
1391.
LETTERS
TO THE EDITOR
Synthesis of 1,3,4-Thiazaphosphols
Containing Aminocarboxylic Acid Fragments in the Molecule
M. A. Pudovik, R. Kh. Bagautdinova, and D. A. Pudovik
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
fax: (+7432) 752253
e-mail: pudovik@iopc.knc.ru
Received December 18, 2008
DOI: 10.1134/S1070363209080283
Amino acids, their derivatives, and phosphorus
analogs exhibit biological activity of a broad spectrum
[1, 2]. In this connection linear and cyclic derivatives
of the tetracoordinated phosphorus involving
aminocarboxylic acid fragments are of undoubted
interest. Recently we have shown that the reaction of
amine hydrochlorides with chloromethylthiophos-
phonylated isothiocyanates in the presence of a base
gives rise to 1,3,4-thiazaphosphols [3]. We used this
approach to synthesize the ring structures containing
phosphorus atom and the fragments of optically active
aminocarboxylic acids.
R1
R1
S
S
PhO
PhO
Et3N
*
*
HCl H NCHC(O)OR
PNCS +
PNHC(S)NHCHC(O)OR
2
.
HCl
−Et3N
ClCH2
ClCH2
IIIа−IIIc
I
IIа−IIc
R1
S
R1
*
S
N
Et3N
S
*
+
C
NH
C
P
P
C(O)OR
.
HCl
−Et3N
C
NH
C
PhO
N
PhO
S
C(O)OR
H
H
RCRP
RCSP
IVа−IVc
IVа−IVc
II–IV, R = R1 = Me (а); R = Et, R1 = CH2Ph (b); R = Me, R1 = CHMe2 (c).
The optically pure aminocarboxylate hydro-
chlorides IIa–IIc were involved into the reaction with
isothiocyanatothiophosphonate. Reaction occurs through
intermediate formation of thioureas IIIa–IIIc, which
rapidly undergo ring closure into 1,3,4-thiazaphos-
phols IVa–IVc in the presence of a base. Since in the
end product molecules there are two chiral centers,
they are formed as pairs of diastereomers. In the case
of alanine and phenylalanine derivatives diastereomers
IVa and IVb are formed in equal amount that indicates
a low stereospecificity of these processes. When L-
valine methyl ester IIc containing rather bulky
isopropyl group was used in the reaction with
isothiocyanate I, the diastereomers ratio in a crude
mixture was 65:35%. The prevailing diastereomer was
isolated by fractional recrystallization from solution.
Recently we have shown that in the reaction of chiral
isothiocyanate
I
with optically active phenyl-
ethylamine the binding of enantiomer having inverse
configuration of chiral centre is preferred [4]. Based on
these data it is likely that the isolated enantiomer IVc
contains chiral centers with the configuration RCSP . Its
rotation angle equals 120º.
4-Phenoxy-4-thioxo-2-(methylmethoxycarbonyl-
methyl)amino-1,3,4-thiazaphosphol (IVа). To a solu-
1748

SYNTHESIS OF 1,3,4-THIAZAPHOSPHOLS
1749
tion of 0.85 g of hydrochloride of L-alanine methyl
ester IIa in 25 ml of anhydrous methylene chloride
was added a mixture of 1.22 g of triethylamine and
1.61 g of isothiocyanate I under stirring and cooling to
0°С. After 2 days the solvent was removed and to the
residue was 10 ml of benzene was added. The
precipitate of triethylamine hydrochloride was
separated and benzene solution was washed with
distilled water thrice by 10 ml and dried over
anhydrous sodium sulfate. After 12 h the solid
component was separated and benzene was removed
under a water-jet pump vacuum. Yield 1.1 g (55%),
pale yellow viscous liquid (diastereomers mixture in a
ratio 53:47%). 1Н NMR spectrum [(СD33)2СO], δ, ppm:
(dominant isomer) 1.48 d (3H, CH3C, JHH 7.65 Hz),
3.54 d.d (1H, РCHA, 2JPH 9.45 Hz, 2JHH 13.10 Hz), 3.72
tion of 0.93 g of L-valine hydrochloride IIc in 20 ml
anhydrous methylene chloride was added a mixture of
1.2 g of triethylamine and 1.47 g of isothiocyanate I
under stirring and cooling to 0°С . After 2 days the
solvent was removed under water-jet pump vacuum
and to the residue was 10 ml of benzene added. The
precipitate of triethylamine hydrochloride was
separated, benzene was removed and the precipitated
product was separated. Yield 0.21 g (11%, optically
pure compound), mp 163–165ºC, [α]2D0 –125.5º (c 0.8,
CH3CN). IR spectrum, ν, cm–1: 698 (P=S), 1218
(POPh), 1566 (C=N), 1593 (Ph), 1735 (C=O), 3349
1
(NH). Н NMR spectrum [(СD3)2СO], δ, ppm: 1.02 d
(6H, CH3C, 3JHH 6.74 Hz), 2.24 m (1H, CHCH3), 3.54
2
2
d.d (1H, РCHA, JPH 9.45 Hz, JHH 13.64 Hz), 3.73 s
2
2
(3H, CH3O), 3.90 d.d (1H, РCHB, JPH 3.15 Hz, JHH
13.64 Hz), 4.59 d (1Н, CHN, 3JHH 4.44 Hz), 7.17–7.36
m (5H, Ph), 8.11 br.s (1H, NH). 31Р NMR spectrum
[(СD3)2СO], δР, ppm: 117.96. Found, (%): C 47.13; H
5.53; N 8.15; P 8.53; S 17.63. C14H19N2O3PS2.
Calculated, (%): С 46.90; H 5.35; N 7.82; P 8.64; S
2
2
s (3H, CH3O), 3.92 d.d (1H, РCHB, JPH 3.15 Hz, JHH
13.10 Hz), 4.68 q (1Н, CHN, 3JHH 7.20 Hz), 7.18–7.38
m (5H, Ph), 8.12 br.s (1H, NH); (minor isomer) 1.46 d
3
2
(3H, CH32C, JHH 7.20 Hz), 3.55 d.d (1H, РCHA, JPH
9.46 Hz, JH2H 13.51 Hz), 3.71 s (3H, CH3O), 3.89 d.d
2
1
(1H, РCHB, JPH 3.15 Hz, JHH 13.51 Hz), 4.74 q (1Н,
17.89. By the H NMR spectrum data, the rest part of
3
CHN, JHH 7.20 Hz), 7.18–7.38 m (5H, Ph), 8.12 br.s
product, yellow viscous liquid, is a diastereomers
mixture in the ratio 56:44%.
(1H, NH). 31Р NMR spectrum [(СD3)2СO], δР, ppm:
117.99. Found, %: C 43.98; H 4.17; N 8.10; P 9.00; S
19.01. C12H15N2O3PS2. Calculated, %: С 43.62; H
4.58; N 8.48; P 9.38; S 19.41.
The IR spectra were registered on a UR-20
spectrometer in the range of 400–3600 сm–1 (mineral
1
oil). The H NMR spectra were measured on a Bruker
4-Phenoxy-4-thioxo-2-(benzylethoxycarbonylme-
thyl)amino-1,3,4-thiazaphosphol (IVb) was prepared
similarly from 1.26 g of L-phenylalanine IIb
hydrochloride, 1.10 g of triethylamine, and 1.46 g of
isothiocyanate I. Yield 1.2 g (52%), pale yellow
viscous liquid (diastereomers mixture in a ratio
AVANCE-600 spectrometer (600 МHz). The 31Р
NMR spectra were taken on a Bruker MSL-400 NMR-
Fourier spectrometer (100.62 MHz).
ACKNOWLEDGMENTS
1
52:48%). Н NMR spectrum [(СD3)23СO], δ, ppm:
This work was financially supported by the Russian
Foundation for Basic Research (grant no. 09-03-
00029).
(dominant isomer) 1.22 t (3H, CH3C, JHH 7.20 Hz),
3.19 m (2H, CH2Ph), 3.53 d.d (1H, РCHA, 2JPH 4.05 Hz,
2
2
2JHH 5.40 Hz), 3.89 d.d (1H, РCHB, JPH 3.50 Hz, JHH
5.40 Hz), 4.13 q (2H, CH2O, 2JHH 6.85 Hz), 4.92 t (1Н,
3
CHN, JHH 7.20 Hz), 7.14–7.35 m (5H, Ph); (minor
REFERENCES
isomer) 1.18 t (3H, CH3C, 3JHH 7.20 Hz), 3.19 m (2H,
2
2
1. Grinshtein, J. and Vinnic, M., Khimiya aminokislot i
peptidov (Aminoacids and Peptides Chemistry),
Moscow: 1965, p. 89.
CH2Ph), 3.52 d.d (1H, РCHA, JPH 4.05 Hz, JHH
13.52 Hz), 3.86 d.d (1H, РCHB, JPH 5.97 Hz, JHH
2
2
2
13.51 Hz), 4.17 q (2H, CH2O, JHH 7.20 Hz), 4.99 t
(1Н, CHN, JHH 6.30 Hz), 7.14–7.35 m (5H, Ph). 31Р
3
2. Kukhar’, V.P. and Solodenko, V.A., Usp. Khim., 1987,
NMR spectrum [(СD3)2СO], δР, ppm: 117.88. Found,
%: C 54.50; H 5.16; N 6.71; P 7.21; S 14.95.
C19H21N2O3PS2. Calculated, %: С 54.26; H 5.04; N
6.66; P 7.37; S 15.25.
vol. 56, no. 9, p. 1504.
3. Pudovik, M.A. and Bagautdinova, R.Kh., Zh. Obshch.
Khim., 2007, vol. 77, no. 8, p. 1393.
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Al’fonsov, and Pudovik, A.N., Synlett., 2006, no. 10,
p. 1613.
4-Phenoxy-4-thioxo-2-(isopropylmethoxycarbonyl-
methyl)amino-1,3,4-thiazaphosphol (IVc). To a solu-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 8 2009