Thiocyanatocarbonyl compounds. the reaction of phosphoryl-α-thio- cyanatoacetaldehydes and their acetals with diethylamine

Article abstract of DOI:10.1007/s10593-009-0232-8

The reactions of phosphorylated α-thiocyanatoacetaldehydes and their acetals with diethylamine were studied for the first time. These reactions result in the synthesis of C-phosphorylated thiazolidine rings.

Full text of DOI:10.1007/s10593-009-0232-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 1, 2009
THIOCYANATOCARBONYL COMPOUNDS.
THE REACTION OF PHOSPHORYL-α-THIO-
CYANATOACETALDEHYDES AND THEIR
ACETALS WITH DIETHYLAMINE
Kh. A. Asadov1*, G. G. Mikailov2, S. N. Guseinova2, R. N. Burangulova1,
R. J. Valiullina1, A. M. Magerramov2, and F. I. Guseinov1
The reactions of phosphorylated α-thiocyanatoacetaldehydes and their acetals with diethylamine were
studied for the first time. These reactions result in the synthesis of C-phosphorylated thiazolidine rings.
Keywords: O,N-acetals, sodium diethylamide, diethylamine, thiazolidines, thiazoline, thiocyanato-
acetals, phosphorylated α-thiocyanatoaldehydes.
Derivatives of thiazole and its hydrogenated analog, thiazolidine, hold an important position among
biologically active heterocycles containing both nitrogen and sulfur atoms. Many functional derivatives of these
heterocycles are commonly used in medicine as immunomodulators and as antimicrobial and antiparasitic drugs
[1].
α-Thiocyanatocarbonyl compounds, particularly, thiocyanatoketones, are convenient key reagents in the
synthesis of thiazole and thiazolidine heterocycles [2-10]. The use of phosphorylated α-thiocyanatoaldehydes as
starting substrates in synthesis of analogous objects has not been described in the literature. Furthermore, the
introduction of the pharmacophoric phosphoryl group into such rings is rather problematical.
The reaction of aldehydes 1, for which we have previously developed preparative methods of synthesis
[11], with diethylamine proceeds exclusively at the aldehyde group regardless of the amount of the amine to
give O,N-acetals 2 (Table 1).
1
The course of the reactions was monitored by H NMR and IR spectroscopy. A colorless abundant
1
precipitate is formed upon mixing the reagents in CCl4. The H NMR spectrum of the precipitate lacks the
aldehyde group doublet at 9.1-10.0 ppm but shows a doublet at 4.55 ppm (3JPH = 12.5 Hz) characteristic for the
semiaminal methine proton. The IR spectrum of zwitterion 3 lacks the aldehyde group band (1710-1740) and
shows a stretching band at 2584 cm-1 characteristic for ammonium groups.
_______
* To whom correspondence should be addressed, e-mail: esedoglu@mail.ru.
1Kazan State Technological University, Kazan 420015, Russia.
2Baku State University, Baku AZ-1148, Azerbaijan; e-mail: mikail05@mail.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 124-130, January, 2009. Original
article submitted November 6, 2007.
0009-3122/09/4501-0105©2009 Springer Science+Business Media, Inc.
105

O
O
(EtO)2P
X
O
(EtO)2P
X
O
O
S
(EtO)2P
SCN
SCN
H
∆
SCN
CHO
(EtO)2P
+ Et2NH
H
C
+
X
NH
C
NEt2
NHEt2
X
_
1a,b
OH
Et2N
4a,b
H
O
2a,b
3a,b
1–4 a X = CO2Et, b X = Ph
Heating compound 2 in toluene at reflux leads to intramolecular heterocyclization and formation of
C-phosphorylated thiazolidine 4, which is a yellow oil with good solubility in many organic solvents. The
heterocyclization of semiaminals 2 proceeds with participation of the OH group and thiocyanate fragment. The
reactions are complete after 10 h at 105-110°C.
Table 2 shows that in going from the IR spectrum of 2 to the spectrum of 4 (Table 2), the absorption
band at 2584 cm-1 for +NHEt2 disappears, while a strong stretching band for the secondary amino group arises at
2981 cm-1 as well as a band at 1679 cm-1 characteristic for the C(2)=O group. The deformation bands for the
phosphoryl group in heterocycles 4 are found at 1264 cm-1 in comparison with 1264 cm-1 for O,N-acetals 2. The
lack of the SCN group band at 2130-2160 cm-1 indicates the participation of this molecular fragment in
cyclization.
TABLE 1. Characteristics of Products Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
N
P
S
2а
2b
4а
4b
6а
6b
7а
7b
C14H27N2О6РS
C17H27N2О4РS
C14H27N2О6РS
C17H27N2О4РS
C18H37N2О7РS
C21H37N2О5РS
C16H31N2О6РS
C19H31N2О4РS
7.26
7.33
7.36
7.25
8.17
8.12
8.14
8.03
8.11
8.38
8.38
8.29
145-146
136-138
Oil
65
62
7.16
7.33
8.07
8.12
8.46
8.38
60
7.26
7.25
8.10
8.03
8.36
8.29
Oil
72
6.17
6.14
6.74
6.80
7.18
7.02
Oil
82
6.06
6.09
6.70
6.74
6.88
6.96
Oil
86
6.96
6.83
7.69
7.56
7.75
7.80
157-159
149-152
65 (59)*
68 (62)*
6.69
6.76
7.50
7.49
7.75
7.73
_______
* The yield in the synthesis from acetales 5 and sodium diethylamide.
3
The signal for the methine proton appears as a doublet of doublets at 5.0-5.2 ppm with JPH = 12.5 and
3JHH = 15 Hz in the 1H NMR spectrum of compound 4 (Table 2), while the signal of the secondary amino group
is seen as a singlet at 8.0 ppm. Such a strong downfield shift of the methine proton signal from 4.55 to
5.0-5.2 ppm indicates intramolecular heterocyclization. The finding of two phosphorus atom signals in the
31P NMR spectrum of thiazolidines 4 indicates the formation of a mixture of diastereomers (Table 2).
106

107

The results concerning the reaction of phosphorylated α-thiocyanatoaldehydes 1 with diethylamine are
rather interesting since an analysis of the literature showed that similar reactions of monohaloacetic and
dihaloacetic analogs of aldehydes 1 with secondary amines at room temperature proceed through a haloform
decomposition scheme with clevage of the C–CHO bond in the aldehyde and the corresponding formylated
amine [12, 13]. This behavior is apparently related to the circumstance that, in the case of halocarbonyl analogs,
the stability of the zwitterion product of the addition of the amine to the aldehyde group increases due to the
enhanced stability of the ammonium fragment. In this case, clevage of the weakened C(Hal)–C bond becomes
more advantageous and proceeds more rapidly than clevage of the N–H bond. When the halogen is replaced by
the less electron-withdrawing thiocyanato fragment, the haloform decomposition does not take place.
The direction of the reaction is different in the reaction of acetals 5, obtained upon the treatment of
aldehydes 1 by triethyl orthoformate in an acid medium [14], with diethylamine. The amino group adds to the
highly polarized C≡N bond to give phosphorylated derivatives of thioureas 6, which are converted to
thiazolines 7 upon heating in xylene at reflux. Thiocyanatoacetals 5 cyclize to give heterocycles 7 also upon the
action of sodium diethylamide.
Thioureas 6 are semicrystalline oils, while thiazolines 7 are crystalline compounds (Table 1).
O
NH
Et2NH
(EtO)2P
C
NEt2
S
X
CH(OEt)2
O
6a,b
∆
(EtO)2P
SCN
O
X
CH(OEt)2
_
+
(EtO)2P
NEt2
Et2N Na
S
5a,b
X
H
N
EtO
7a,b
5–7a X = CO2Et, b X = Ph
The IR spectra of thioureas 6 and thiazolines 7 show strong bands for the C–O–C (1150), C=N (1635),
and C=O groups (1680 cm-1). The P=O group stretching vibrations are seen as weak signals at 1232 cm-1 for
compounds 6 and 1262 cm-1 for compounds 7. The absorption band for the =NH group in thioureas 6 is seen in
the vicinity of 2870 cm-1.
The 1H NMR spectra of thioureas 6 in acetone-d6 show a doublet at ~5.25 ppm (3JPH = 2.5 Hz) assigned
to the acetal group proton. The small coupling constant for CH–O group proton may be due to the effect of steric
factors on the dihedral angle. The imino group proton signal is a broad singlet at 7.7 ppm. Thiazolines 7 have a
singlet at 5.07 ppm corresponding to H-2 in addition to the characteristic signals of the ethyl and ethoxyl groups.
The lack of the singlet for the imino group proton at 7.7 ppm and the integral intensities of the signals of the EtO
fragment are evidence for the cyclization of thioureas 6 involving the =NH and EtO groups and loss of EtOH.
31
The assignment of all the other signals is given in Table 2. The P NMR spectrum features phosphorus atom
signals from two diastereomers at 16.04 and 17.54 ppm. We should note that the physicochemical characteristics
of thiazolines 7 obtained by both pathways are identical.
108

EXPERIMENTAL
1
The IR spectra were taken for vaseline mulls or KBr pellets on a UR-20 spectrometer. The H NMR
spectra were taken on a Tesla BW-567 spectrometer at 200 MHz with HMDS as the internal standard and a
Bruker MSL-600 spectrometer at 600 MHz with HMDS as the internal standard. The 31P NMR spectra were
taken on a Bruker MSL-400 spectrometer at 162 MHz with 85% H3PO4 as the standard.
Diethyl Ester of 2-Diethylamino-2-hydroxy-1-phenyl-1-thiocyanatophosphonic Acid (2b). A
10% excess of diethylamine (0.8 g, 0.011 mol) in CCl4 (5 ml) was added with stirring to a solution of
thiocyanatoaldehyde 1b (3.13 g, 0.01 mol) in absolute CCl4 (15 ml). The reaction mixture was stirred for 5 h at
room temperature. The colorless abundant precipitate formed was filtered off and washed with cold ether to give
2.39 g 2b as white crystals.
Diethyl Ester of 2-Diethylamino-1-ethoxycarbonyl-2-hydroxy-1-thiocyanatophosphonic Acid (2a)
was obtained analogously.
5-Diethoxyphosphoryl-4-diethylamino-2-oxo-5-phenyl-4,5-thiazolidine (4b).
A
solution of
compound 2b (3.86 g, 0.01 mol) in toluene (15 ml) was heated at reflux for 10 h. The solvent was removed to
give heterocycle 4b (2.78 g) as an oil.
5-Diethoxyphosphoryl-4-diethylamino-5-ethoxycarbonyl-2-oxo-4,5-thiazolidine (4a) was obtained
analogously.
Diethylacetal of 2-Diethoxyphosphoryl-2-(1-imino-1-diethylaminomethyl)-2-phenylthioacetalde-
hyde (6b). A solution of thiocyanatoacetal 5b (3.87 g, 0.01 mol) and diethylamine (0.8 g, 0.011 mol,
10% excess) in absolute benzene (30 ml) was heated at reflux for 8 h. Removal of the solvent gave compound
6b (3.96 g) as a wine-colored semicrystalline oil.
Diethylacetal of 2-Diethoxyphosphoryl-2-ethoxycarbonyl-2-(1-imino-1-diethylaminomethyl)thio-
acetaldehyde (6a) was obtained analogously.
2-Diethylamino-4-ethoxy-2H,5H-5-diethoxyphosphoryl-5-phenyl-1,3-thiazoline (7b). A solution of
acetal 6b (4.602 g, 0.01 mol) in absolute dioxane (10 ml) was heated at reflux for 8 h. The solvent was removed
in vacuum and 10 ml 1:1 petroleum ether–benzene was added to the oil obtained. The crystalline precipitate
formed (2.82 g) was filtered off, recrystallized from acetonitrile, and dried.
2-Diethylamino-4-ethoxy-5-ethoxycarbonyl-2H,5H-5-diethoxyphosphoryl-1,3-thiazoline (7a) was
obtained analogously.
Synthesis of Thiazolines 7 by the Reaction of Acetals 5 with Sodium Diethylamide. Diethylamine
(0.73 g) in benzene (5 ml) was added dropwise to metallic sodium (0.23 g, 0.01 mol) in absolute benzene
(5 ml). The reaction mixture was stirred a 70-80°C until the sodium was completely dissolved. A solution of
0.01 mol corresponding acetal 5 was added dropwise to the salt obtained and heated at reflux for 10 h. After
removal of the solvent, the oil obtained was dissolved in ether. The crystalline precipitate was filtered off, dried
in the air, and recrystallized from acetonitrile or 1:1 ethanol–water. The yields of thiazolines 7a and 7b are given
in Table 1.
This work was carried out with the financial support of the Russian Basic Research Fund (Grant
07-03-00316-a) and Russian Federation President's Grant (MK-4043.2007.3).
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