Reactions of tert-butyl N,N-diethyl-N′-(4-phenylthiazol-2-yl)- phosphorodiamidite with electrophilic reagents

Article abstract of DOI:10.1134/S1070363206090076

Previously unknown amidophosphorous acid derivatives were prepared by transamidation of tert-butyl N,N-diethyl-N′-(4-phenylthiazolyl) phosphorodiamidite with 2-amino-4-phenylthiazole, and their reactions with acetyl and benzoyl chloride were studied. Thes

Full text of DOI:10.1134/S1070363206090076

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 9, pp. 1397 1400.
Pleiades Publishing, Inc., 2006.
Original Russian Text L.K. Sal’keeva, M.T. Nurmaganbetova, E.V. Minaeva, B.Z. Kokzhalova, 2006, published in Zhurnal Obshchei Khimii, 2006,
Vol. 76, No. 9, pp. 1456 1459.
Reactions of tert-Butyl N,N-Diethyl-N -(4-phenylthiazol-2-yl)-
phosphorodiamidite with Electrophilic Reagents
L. K. Sal’keeva, M. T. Nurmaganbetova, E. V. Minaeva, and B. Z. Kokzhalova
Buketov Karaganda State University, ul. Universitetskaya 28, Karaganda, 100026 Kazakhstan
e-mail: L.Salkeeva@kargu.krg.kz
Received May 3, 2006
Abstract Previously unknown amidophosphorous acid derivatives were prepared by transamidation of
tert-butyl N,N-diethyl-N -(4-phenylthiazolyl)phosphorodiamidite with 2-amino-4-phenylthiazole, and their
reactions with acetyl and benzoyl chloride were studied. These reactions are shown to proceed regioselectively
according to the Arbuzov scheme to give the corresponding ketophosphonates. The reaction of the phosphoro-
diamidite with acetyl chloride in a 1: 2 molar ratio involves formation of acetophosphonate that reacts in the
enol form to give the corresponding (1-acetoxy)vinylphosphonate.
DOI: 10.1134/S1070363206090076
One of the most important and promising direc-
tions of the synthesis of biologically active compound
is chemical modification of previously known com-
pounds having pharmacophoric groups, such as re-
adily available 2-aminothiazole derivatives. Thiazoles
and their derivatives are known to exhibit pharmaco-
logical activity. Among them, antimicrobial, anti-
histaminic, antiparasitic, antihelminthic, antipyretic,
and antiviral preparations were found. Norsulfazol,
phthalazol, and related compounds are thiazole deriva-
tives widely used in medical practice. The thiazole
ring is present in such natural compounds as vitamin
B1 (thiamine), penicillin, and carboxylase enzyme [1].
Thiazole series compounds are widely used as anti-
oxidants for petroleum products, vulcanization ac-
celerators, and photochromic compounds [2, 3].
Attempts to prepare phosphorus-containing deriva-
tives of thiazole and its homologs were undertaken at
different times. Specifically, attempted involvement
of 2-aminothiazole in direct condensation with
aromatic aldehydes and dialkyl hydrogen phosphites
in the presence of alkali metal alkoxides failed, evi-
dently because of its low basicity (pKa 5.39) [4].
2-Aminothiazole could be phosphonomethylated with
the dialkyl hydrogen phosphite benzaldehyde diethyl
acetal system in presence of boron trifluoride etherate
[5]. The possibility of equilibrium between the amino
and imino forms was shown, and the fact that the
equilibrium is strongly shifted to the amino form was
established.
O
N
N
EtO
HO
BF3 Et2O
(EtO)2PHO + PhCH(OEt)2 +NH2
O
P CH NH
S
S
Ph
N
H
O
N
EtO
EtO
P CH N
Ph
P CH NH
H
S
HO
HO
S
Ph
amino form
imino form
We previously showed that transamidation of tert-
butyl tetraethylphosphorodiamidite (I) with 2-amino-
4-phenylthiazole (II) results in formation of pre-
viously unknown tert-butyl N,N-diethyl-N -(4-phenyl-
thiazol-2-yl)phosphorodiamidite (III) [6].
The imino form of phosphorodiamidite III is even
less possible, because the phenyl radical significantly
decreases the basicity of the thiazole amino group.
The reaction was carried out by heating equimolar
1397

1398
SAL’KEEVA et al.
(Et2N2)POBu-t +
N
N
+ Et2NH
NH2
NH P NEt2
I
S
S
OBu-t
II
III
amounts of phosphorodiamidite I and 2-amino-4-
phenylthiazole in ethyl acetate with simultaneous
distillation of diethylamine. The latter was identified
as hydrochloride. The reaction progress was moni-
tored by TLC. The amount of the hydrochloride
formed characterized the reaction completion. Com-
pound III was purified by crystallization from
benzene. It is a white crystalline substance soluble in
water and polar solvents.
such structures can exhibit dual reactivity. In view of
known factors, we considered it interesting to study
the behavior of phosphoroamidite III in the Arbuzov
reaction with various electrophiles. Hence, by reacting
compound III with acetyl chloride under various
conditions we showed that the reaction proceeds regio-
selectively by the P(III) atom to give the correspond-
ing acetylphosphonic diamide IV. The process is ac-
companied by liberation of equimolar amount of iso-
butylene. The reaction mechanism evidently includes
the nucleophilic attack of the phosphorus atom, lead-
ing to a quasiphosphonium compound of the penta-
covalent or ionic structure, depending on the nature
of the solvent. The quasiphosphonium intermediate
quickly decomposes with isobutylene liberation. Its
amount was established volumetrically. Indirect
evidence for the proposed mechanism is provided by
the isolation of equimolar amount of triethylamine
hydrochloride in the reaction in presence of triethyl-
amine. The structure of acetylphosphonic diamide IV
was confirmed by the formation of a colored hydra-
zone precipitate under the action of 2,4-dinitrophenyl-
hydrazine.
Transamidation of phosphorodiamidite I with two
mol of thiazole II resulted in liberation of one mole of
diethylamine only. After addition of one more mole of
compound I, phosphorodiamidite III was isolated and
identified. Hence, two 2-amino-4-phenylthiazole
groups cannot be introduced to the P(III) atom,
probably, by steric reasons. Phosphorodiamidite III
was further used for chemical modification.
Compound III has a polyfunctional structure due
to the simultaneous presence of a P(III) atom, on the
one hand, and nucleophilic diethylamino and amino-
thiazolyl nitrogen atoms on the other. As known [7],
N
+ CH3COCl
NH P NEt2
OBu-t
S
III
NEt2
NH P+ COCH3 Cl
NEt2
Cl
N
N
NH P COCH3
S
S
OBu-t
OBu-t
NEt2
N
(CH3)2C=CH2
HCl
+ t-BuCl
NH P C CH3
S
O
O
IV
Et3N
IV + (CH3)2C=CH2
Et3N HCl
The structure of phosphonate IV suggests existence
of the enol form in equilibrium with the keto form.
To obtain evidence for this possibility, we treated
phosphorodiamidite III with acetyl chloride in a 1:2
molar ratio and also in presence of two mole of tri-
ethylamine. It was found that diamide IV formed in
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 9 2006

REACTIONS OF tert-BUTYL N,N-DIETHYL-N -(4-PHENYLTHIAZOL-2-YL)PHOSPHORODIAMIDITE
1399
The reaction of phosphorodiamidite III with
benzoyl chloride proceeds analogously to give the
corresponding benzoylphosphic diamide in high yield.
This result is evidently explained by the fact that the
resulting benzoylphosphic diamide cannot be further
benzoylated, because it lacks, unlike acetylphosphonic
diamide IV, the enol form.
O2N
NH P C=N NH
IV2,4-DNPH
NEt2
N
NO2
S
O
CH3
V
the first stage reacts in the enol form with the second
acetyl chloride molecule to give acetoxyvinylphos-
phonic diamide VI.
Continuing these investigations, we performed re-
action of phosphorodiamidite III reaction with phenyl
isothiocyanate to obtain phosphorylated phenylthio-
carbamate VII in high yield. It is a stable substance
readily soluble in organic solvents. Compound VII
present interest in terms of biologic activity.
IV + CH3COCl
Et3N
CH2
O
N
Et3N HCl
NH P C OCOCH3
S
NEt2
VI
NEt2
N
N
NH P NEt2 + PhN=C=S
NH P+
C
S
S
S
OBu-t
OBu-t
NPh
III
NEt2
N
NEt2
NH P C NH Ph
N
NH P+
O
C
S+ t-Bu+
S
S
S
O
NPh
VII
EXPERIMENTAL
1H NMR spectrum, , ppm: 7.22 7.48 m (CH, C6H5),
1.21 s [9H, (CH3)3C], 1.07 t (6H, CH3, JHH 7 Hz),
3
The IR spectra were recorded on Specord IR-75
2.59 m (4H, CH2), 4.0 (1H, NH). Found, %: C 58.45;
H 7.22; N 11.78; P 8.98. C17H26NO3PS. Calculated,
%: C 58.12; H 7.40; N 11.96; P 8.83; S 9.12.
1
spectrometer (3700 400 cm , thin film) and Nicolet
1
Avator-360 instruments. The H NMR spectra were
taken on a Bruker DRX-500 spectrometer (500 MHz)
against internal TMS.
N,N-Diethyl-N -(4-phenylthiazol-2-yl)(acetyl)-
phosphonic diamide (IV). To a solution of 7.02 g of
compound III in benzene, 1.57 g of acetyl chloride
was added, and the resulting mixture was refluxed.
Isobutylene liberated and was measured volumetri-
cally. The liberated amount, 412 ml (92%), is stoi-
chiometric. The precipitate formed was filtered off
and crystallized from ethanol to give 5.05 g (75%) of
tert-Butyl N,N-diethyl-N -(4-phenylthiazol-2-yl)-
phosphorodiamidite (III). tert-Butyl tetraethylphos-
phorodiamidite, 4.96 g, was treated with 3.52 g of
2-amino-4-phehylthiazole in 100 ml of ethyl acetate.
The reaction mixture was heated until diethylamine
no longer distilled. The amount collected, 1.34 g
(92%), was stoichiometric. The diethylamine obtained
was identified as hydrochloride, mp 221 C (reference
data: mp 221 C). Free diethylamine, bp 54 55 C, nD20
1.3873 (reference data: bp 55.5 C, n2D0 1.3878), was
isolated by treatment with alkali. Compound III was
purified by crystallization from benzene. Yield 5.97 g
1
compound IV, mp 178 C. IR spectrum, , cm :
1462, 1599 (C=C), 1623 (C=O), 3375 (NH), 1203
(P=O). Found, %: C 53.12; H 5.40; N 12.54; P 9.43;
S 9.22. C15H20N3O2PS. Calculated, %: C 53.41; H
5.93; N 12.46: P 9.20; S 9.50.
[(Diethylamino)[(4-phenylthiazol-2-yl)amino]-
phosphinoyl](methylene)methyl acetate (VI). To a
solution of 7.02 g of compound III and 4.04 g of tri-
1
(85%), mp 141 142 C. IR spectrum, , cm : 1475,
1620, (C=C), 1685 (C=N), 3365 (NH), 1060 (P O C).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 9 2006

1400
SAL’KEEVA et al.
ethylamine in benzene, 3.14 of acetyl chloride was
added at 20 C. The resulting mixture was refluxed
until 421 ml (94%) of isobutylene liberated (by
volumetry). The precipitate formed was filtered off
and washed with several portions of distilled water to
remove triethylamine hydrochloride and then crystal-
lized from ethanol to obtain 6.06 g (80%) of com-
2. Comprehensive Organic Chemistry, Barton, D.H. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 4.
Translated under the title Obshchaya organicheskaya
khimiya, Moscow: Khimiya, 1985, vol. 9, p. 481.
3. Uchikawa, O., Fukatsu, K., and Suno, M., Chem.
Pharm. Bull., 1996, vol. 44, no. 11, p. 2070.
1
4. Prokof’ev, A.F., Aleshnikova, T.N., Negrebetskii, V.V.,
Grapov, A.F., and Mel’nikov, N.N., Zh. Obshch. Khim.,
1984, vol. 54, no. 3, p. 525.
pound VI, mp 205 206 C. IR spectrum, , cm :
1442, 1549 (C=C), 1644 (C=O), 3167 (NH), 1302
(P=O). Found, %: C 53.76; H 5.67; N 11.26; P 8.56;
S 8.32. C17H22N3O3PS. Calculated, %: C 53.83; H
5.80; N 11.08; P 8.18; S 8.44.
5. Albert, A., Goldacre, R.J., and Phillips, J., J. Chem.
Soc., 1948, p. 2240.
6. Sal’keeva, L.K., Nurmaganbetova, M.T., and Minae-
va, E.V., Zh. Obshch. Khim., 2005, vol. 75, no.
12, p. 2065.
REFERENCES
1. Zbarskii, B.I., Ivanov, I.I., and Mardashev, S.R.,
Biologicheskaya khimiya (Biological Chemistry),
Leningrad: Meditsina, 1972, p. 171.
7. Ivanov, B.E. and Zheltukhin, V.F., Usp. Khim., 1970,
vol. 39, no. 5, p. 773.
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