A Facile Synthesis of Derivatives of (1,3,4-Thiadiazol-2-yl)glycine and Its Phosphonyl Analogue

Article abstract of DOI:10.1055/s-2003-42458

The adducts formed by 4-functionally-substituted 2-aryl-5-hydrazino-1,3- oxazoles and aryl isothiocyanates recyclize on heating to produce the hitherto unknown derivatives of (1,3,4-thiadiazol-2-yl)glycine and its phosphonyl analogue.

Full text of DOI:10.1055/s-2003-42458

PAPER
2851
A Facile Synthesis of Derivatives of (1,3,4-Thiadiazol-2-yl)glycine and Its
Phosphonyl Analogue
Synthesis of
D
eriv
l
a
tives
o
e
f
(1, 3,4-Th
k
iadiazol-2-y
s
l)glycine andr V. Golovchenko,a Stepan G. Pilyo,a Vladimir S. Brovarets,*a Alexander N. Chernega,b Boris S. Dracha
a
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska str. 1, Kyiv-94,
02094, Ukraine
Fax +380(44)5732561; E-mail: Drach@bpci.kiev.ua
b
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska str. 5, Kyiv-94, 02094, Ukraine
Fax +380(44)5732643
Received 23 July 2003; revised 29 September 2003
S(1)N(1)N(2)C(1)C(2)
makes
with
the
Abstract: The adducts formed by 4-functionally-substituted 2-aryl-
5-hydrazino-1,3-oxazoles and aryl isothiocyanates recyclize on
heating to produce the hitherto unknown derivatives of (1,3,4-thia-
diazol-2-yl)glycine and its phosphonyl analogue.
N(4)C(2)H(4)C(13) plane dihedral angle of 9.9°, whereas
the C(13–18) benzene ring is twisted out of this plane by
only 4.6°.
Key words: -aminocarboxylic acids
-aminoalkylphosphonic
acids, (1,3,4-thiadiazol-2-yl)glycine, 1,3-oxazoles, 3,3-dichloro-
acrylates, 2,2,2-trichloroethylphosphonates, aryl isothiocyanates
In recent years, modified -aminocarboxylic acids con-
taining heterocyclic substituents at the and positions
relative to the carboxy group have found extensive appli-
cation in biochemical research as well as in the search for
bioactive substances (see recent publications1–6 and refer-
ences therein). Systems of this kind can be exemplified by
-amino acid derivatives containing a pyridine,4,7 pyrimi-
dine,1,3,8 or purine3 residue as well as the fragments of
some five-membered heterocycles such as pyrazole,4,6
1,2-oxazole,4,9 1,2-thiazole,10 1,2,3-triazole,6 and 1,2,5-
thiadiazole.11
Figure 1 Perspective view and labelling scheme for the molecule
5d (S-enantiomer)
We have developed an original synthetic access to the
hitherto unknown functional derivatives of 1,3,4-thiadia-
zol-2-ylglycine starting from previously obtained12 alkyl
2-acylamino-3,3-dichloroacrylates 1a–c as shown in
Scheme 1. First, compounds 1a–c were treated with an
excess of hydrazine hydrate to yield substituted 5-hy-
drazino-1,3-oxazoles 2a–c, whose structures were con-
firmed by IR and 1H NMR spectroscopy (Table 1). Much
the same cyclization was investigated before in the case of
2-acylamino-3,3-dichloroacrylonitriles, the close ana-
logues of compounds 1a–c.13,14
In a crystal of racemate 5d, (R)-enantiomer molecules are
joined into centrosymmetric dimers by the hydrogen
bonds
N(4)–H(4)…N(2)
[N(4)…N(2)
2.891(5),
H(4)…N(2) 1.93(4), and N(4)–H(4) 0.97(5) Å, N(4)H(4)
N(2) 172(2)°]. In turn, the dimers form an endless chain
by means of the hydrogen bonds N(3)-H(3)… O(3) with
(S)-enantiomer molecules [the respective distances and
angle are: N(3)…O(3) 2.928(5), H(3)…O(3) 1.99(4), and
N(3)–H(3) 1.00(4) Å, N(3)H(3)O(3) 155(2)°].
Substrates 2a–c, if reacted with aryl isothiocyanates, first
produce adducts 3a–h apparently able to form prototropic
tautomers 4a–h which recyclize on heating to give the
corresponding (1,3,4-thiadiazol-2-yl)glycine derivatives
5a–h. The molecular structure of compound 5d (Figure 1
and Table 2) was determined by a single-crystal X-ray
diffraction. The S(1)N(1)N(2)C(1)C(2)–N(4)H–C(13–
18) bond system is approximately planar; the deviation
from the least-square plane are in the range 0.009–0.225
Thus, the conversion 3
5 is supported by solid evi-
dence. A similar recyclization leading to 1,3,4-oxadiazole
derivatives has recently been found to occur on heating
the 2-aryl-5-hydrazino-1,3-oxazole-4-carbonitriles in
acetic acid.14 By structural features, the conversion 3
4
5 belongs to a particular rearrangement type studied by
Boulton, Katritzky et al.15 which involves azole side
chains. Of great preparative importance is not only the
conversion 3
4
5 but also further modification of re-
Å
(average 0.092 Å). The thiadiazole ring
cyclization products using sodium hydroxide which fur-
nishes previously unknown 2-acylaminomethyl-5-
arylamino-1,3,4-thiadiazoles 6a,g (Scheme 1).
SYNTHESIS 2003, No. 18, pp 2851–2857
x
x.
x
x
.
2
0
0
3
Advanced online publication: 04.11.2003
DOI: 10.1055/s-2003-42458; Art ID: P06703SS
© Georg Thieme Verlag Stuttgart · New York

2852
A. V. Golovchenko et al.
PAPER
Scheme 1
Table 1 Spectroscopic Data of Compounds 2, 3, 5, 6, 9, 10
Compound IR (KBr) (cm–1) 1H NMR (DMSO-d6/TMS) , J (Hz)
3.75 (s, 3 H, CH3), 4.70 (br s, 2 H, NH2), 7.40–7.88 (m, 5 H, C6H5), 8.09 (br s, 1 H, NH)
2a
2b
1670 (OC=O), 360 (NH, NH2)
1665 (OC=O), 3200 (NH, NH2)
1660 (OC=O), 3320 (NH, NH2)
1660 (OC=O), 3330 (NH)
2.34 (s, 3 H, CH3), 3.71 (s, 3 H, CH3), 4.80 (br s, 2 H, NH2), 7.31–7.73 (m, 4 H, C6H4),
8.27 (br s, 1 H, NH)
2c
3a
3d
5a
5b
5c
5da
5e
1.31 (t, 3 H, CH3), 4.22 (q, 2 H, CH2), 4.74 (br s, 2 H, NH2), 7.18–7.86 (m, 5 H, C6H5),
8.09 (br s, 1 H, NH)
3.80 (s, 3 H, CH3), 7.14–7.83 (m, 10 H, 2 × C6H5), 9.35 (br s, 1 H, NH), 9.93 (s, 1 H,
NH), 10.04 (s, 1 H, NH)
1660 (OC=O), 3330 (NH)
2.27 (s, 3 H, CH3), 3.77 (s, 3 H, CH3), 7.14–7.81 (m, 9 H, C6H5, C6H4), 9.49 (s, 1 H, NH),
9.95 (s, 1 H, NH), 10.03 (s, 1 H, NH)
1645 (NC=O), 1760 (OC=O),
3330 (NH)
3.73 (s, 3 H, CH3), 5.91 (d, 1 H, J = 7.2, CH), 7.00–7.93 (m, 10 H, 2 × C6H5), 9.74 (d, 1
H, J = 7.2, NH), 10.37 (s, 1 H, NH)
1645 (NC=O), 1750 (OC=O),
3290 (NH)
2.36 (s, 3 H, CH3), 3.71 (s, 3 H, CH3), 5.87 (d, 1 H, J = 7.2, CH), 7.00–7.80 (m, 9 H,
C6H5, C6H4), 9.67 (d, 1 H, J = 7.2, NH), 10.36 (s, 1 H, NH)
1630 (NC=O), 1745 (OC=O),
3300 (NH)
1.24 (t, 3 H, CH3), 4.20 (q, 2 H, CH2), 5.77 (d, 1 H, J = 7.2, CH), 6.95–7.93 (m, 10 H,
2 × C6H5), 9.66 (d, 1 H, J = 7.2, NH), 10.29 (s, 1 H, NH)
1665 (NC=O), 1760 (OC=O),
3350 (NH)
2.27 (s, 3 H, CH3), 3.73 (s, 3 H, CH3), 5.79 (d, 1 H, J = 7.2, CH), 7.09–7.92 (m, 9 H,
C6H5, C6H4), 9.67 (d, 1 H, J = 7.2, NH), 10.17 (s, 1 H, NH)
1640 (NC=O), 1750 (OC=O),
3340 (NH)
3.73 (s, 6 H, 2 × CH3), 5.73 (d, 1 H, J = 7.2, CH), 6.85–7.95 (m, 9 H, C6H5, C6H4), 9.64
(d, 1 H, J = 7.2, CH), 10.07 (s, 1 H, NH)
Synthesis 2003, No. 18, 2851–2857 © Thieme Stuttgart · New York

PAPER
Synthesis of Derivatives of (1,3,4-Thiadiazol-2-yl)glycine
2853
Table 1 Spectroscopic Data of Compounds 2, 3, 5, 6, 9, 10 (continued)
Compound IR (KBr) (cm–1) 1H NMR (DMSO-d6/TMS) , J (Hz)
1.24 (t, 3 H, CH3), 2.28 (s, 3 H, CH3), 4.20 (q, 2 H, CH2), 5.76 (d, 1 H, J = 7.2, CH), 7.10–
5f
1645 (NC=O), 1745 (OC=O),
3260 (NH)
7.90 (m, 9 H, C6H5, C6H4), 9.62 (d, 1 H, J = 7.2, NH), 10.18 (s, 1 H, NH)
5g
5h
1635 (NC=O), 1745 (OC=O),
3265 (NH)
2.25 (s, 3 H, CH3), 2.36 (s, 3 H, CH3), 3.70 (s, 3 H, CH3), 5.85 (d, 1 H, J = 7.2, CH), 7.15–
7.82 (m, 8 H, 2 × C6H4), 9.65 (d, 1 H, J = 7.2, NH), 10.25 (s, 1 H, NH)
1645 (NC=O), 1750 (OC=O),
3290 (NH)
2.36 (s, 3 H, CH3), 3.70 (s, 3 H, CH3), 3.72 (s, 3 H, CH3), 5.82 (d, 1 H, J = 7.2, CH), 6.91–
7.80 (m, 8 H, 2 × C6H4), 9.64 (d, 1 H, J = 7.2, NH), 10.14 (s, 1 H, NH)
6a
6g
1645 (NC=O), 3220 (NH)
1640 (NC=O), 3260 (NH)
4.69 (d, 2 H, CH2), 6.96–7.90 (m, 10 H, 2 × C6H5), 9.37 (t, 1 H, NH), 10.26 (s, 1 H, NH)
2.27 (s, 3 H, CH3), 2.37 (s, 3 H, CH3), 4.64 (d, 2 H, J = 6.8, CH2), 7.10–7.76 (m, 8 H,
2 × C6H4), 9.19 (t, 1 H, NH), 10.04 (s, 1 H, NH)
9a
9c
1250 (P=O), 3260 (NH)
–
3.69 (d, 6 H, JH,P = 12.1, 2 × CH3), 4.80 (br s, 2 H, NH2), 7.45–7.86 (m, 6 H, C6H5, NH)
3.67 (d, 6 H, JH,P = 12.0, 2 × CH3), 4.75 (br s, 2 H, NH2), 7.03–7.64 (m, 8 H, C6H5,
CH=CH, NH)
10a
10b
10c
10d
10e
10fa
–
3.50 (d, 6 H, 2 × CH3), 5.56 (m, 1 H, CH), 6.90–8.17 (m, 11 H, 2 × C6H5, NH), 10.22
(br s, 1 H, NH),
1250 (P=O), 1645 (NC=O),
3220 (NH)
2.38 (s, 3 H, CH3), 3.77 (d, 6 H, JH,P = 10.8, 2 × CH3), 6.13 (dd, 1 H, J = 9.3, JH,P = 21.5,
CH), 6.95–7.83 (m, 9 H, C6H5, C6H4), 9.40 (d, 1 H, J = 9.3, NH), 10.30 (s, 1 H, NH)
–
3.76 (t, 6 H, 2 × CH3), 5.97 (dd, 1 H, J = 6.4, JH,P = 16.0, CH), 6.86–7.59 (m, 12 H,
2 × C6H5, CH=CH), 9.29 (d, 1 H, J = 6.4, NH), 10.34 (s, 1 H, NH)
–
1.25 (m, 6 H, 2 × CH3), 4.12 (m, 4 H, 2 × CH2), 6.06 (dd, 1 H, J = 8.3, JH,P = 20.8, CH),
6.97–7.91 (m, 10 H, 2 × C6H5), 9.49 (d, 1 H, J = 8.3, NH), 10.32 (s, 1 H, NH)
1265 (P=O), 1655 (NC=O),
3240 (NH)
1.20 (m, 6 H, 2 × CH3), 4.11 (m, 4 H, CH2), 5.97 (dd, 1 H, J = 7.2, JH,P = 19.0, CH),
6.90–7.59 (m, 12 H, 2 × C6H5, CH=CH), 9.28 (d, 1 H, J = 7.2, NH), 10.42 (s, 1 H, NH)
–
2.28 (s, 3 H, CH3), 2.38 (s, 3 H, CH3), 3.77 (d, 6 H, JH,P = 11.4, 2 × CH3), 6.04 (dd, 1 H,
J = 8.1, JH,P = 20.0, CH), 7.09–7.85 (m, 8 H, 2 × C6H4), 9.40 (d, 1 H, J = 8.1, NH), 10.21
(s, 1 H, NH)
a For compounds 5d and 10f, the respective 13C NMR signals for NC=O, C(2)=N, C(5)=N were registered (DMSO-d6/TMS): = 154.26,
166.36, 168.62 and 153.56, 165.97, 166.26.
Table 2 Selected X-Ray Bond Lengths and Bond Angles of Com-
pound 5d
By analogy with the synthesis of new glycine derivatives
5a–h, we have managed to obtain structurally related
compounds, aminomethylphosphonic acid derivatives
S(1)–C(1)
S(1)–C(2)
N(1)–N(2)
N(1)–C(1)
N(2)–C(2)
N(3)–C(3)
N(3)–C(6)
N(4)–C(2)
N(4)–C(13)
C(6)–C(7)
1.735(4)
1.732(4)
1.383(5)
1.284(5)
1.325(5)
1.463(5)
1.339(5)
1.347(5)
1.409(5)
1.493(5)
C(1)–S(1)–C(2)
N(2)–N(1)–C(1)
N(1)–N(2)–C(2)
C(3)–N(3)–C(6)
C(2)–N(4)–C(13)
S(1)–C(1)–N(1)
S(1)–C(2)–N(2)
87.3(2)
10a–f (Scheme 2). At first, the available N-(1,2,2,2-tetra-
chloroethyl)carboxamides 7a–c were subjected to the Ar-
buzov reaction with trialkyl phosphites and then the
resulting phosphonates 8a–e were treated successively
with excess hydrazine hydrate16 and an equimolar amount
of the corresponding aryl isothiocyanate. The expected re-
113.4(3)
112.1(3)
119.5(3)
130.5(4)
114.1(3)
113.1(3)
action course, namely, the formation of 9 followed by the
1
recyclization 9
10 is corroborated by the H NMR
spectra of the final products 10a–f which suggest the pres-
ence of the characteristic moiety PCHNH (Table 1). Fur-
thermore, 10f like its phosphorus-free analogue 5d,
exhibits two downfield 13C NMR signals ( = >165),
which can be assigned to the atoms C-2 and C-5 of the
electron-deficient 1,3,4-thiadiazole ring. The conversion
9
10 adds to a list of the known methods for the synthe-
sis of hetaryl-substituted -aminoalkylphosphonic acids,
which have been attracting considerable attention recently
in search of various bioregulators (see, e.g., the
monograph17 and the main papers18–22).
Synthesis 2003, No. 18, 2851–2857 © Thieme Stuttgart · New York

2854
A. V. Golovchenko et al.
PAPER
Scheme 2
tallization from benzene; yield: 1.8 g (73%); colorless crystals; mp
122–123 °C.
The applicability and scope for the synthetic approaches
represented in Schemes 1 and 2 as well as modification
aspects for compounds 5 and 10 will be considered else- Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N, 17.00. Found: C,
58.51; H, 5.47; N, 16.85.
where.
Alkyl 2-Aryl-5-(4-arylthiosemicarbazido)-1,3-oxazole-4-car-
boxylates 3a–h; General Procedure
1H and 13C NMR spectra were recorded on a Varian Gemini 300
spectrometer at 300 and 75.43 MHz, respectively, using TMS as an
internal standard. IR spectra were measured on a Specord M-80
spectrometer for KBr discs.
To a solution of compound 2a–c (10 mmol) in anhyd dioxane (20
mL), the corresponding aryl isothiocyanate (10.5 mmol) was added.
The mixture was allowed to stand at r.t. for 72 h. The resulting pre-
cipitate was filtered off, washed with dioxane, and dried in vacuo.
Analytical and spectral data were obtained for compounds 3a,d,
whereas their analogues 3b,c,e–h were immediately used in the
preparation of compounds 5b,c,e–h without isolation (Table 1).
Alkyl 2-Aryl-5-hydrazino-1,3-oxazole-4-carboxylates 2a–c;
General Procedure
To a solution of enamide 1a–c (10 mmol) obtained by the known
procedure12 in MeOH or EtOH (20–30 mL) was added hydrazine
hydrate (35 mmol). The mixture was allowed to stand at r.t. for 24
h. After filtering off hydrazine hydrochloride, the solvent was evap-
orated in vacuo, and the residue was treated with H2O, filtered off,
dried, and purified by recrystallization from MeOH or benzene
(Table 1).
Methyl 2-Phenyl-5-(4-phenylthiosemicarbazido)-1,3-oxazole-4-
carboxylate (3a)
Compound 3a was prepared following the general procedure from
2a (2.33 g) and phenyl isothiocyanate (1.42 g) in anhyd dioxane (20
mL); yield: 3.17 g (86%); colorless crystals; mp 157–158 °C.
Anal. Calcd for C18H16N4O3S: C, 58.68; H, 4.38; N, 15.21; S, 8.70.
Found: C, 58.74; H 4.61; N, 15.06; S, 8.43.
Methyl 5-Hydrazino-2-phenyl-1,3-oxazole-4-carboxylate (2a)
Compound 2a was prepared following the general procedure from
1a (2.74 g) in MeOH (20 mL). The product was purified by recrys-
tallization from MeOH; yield: 1.98 g (85%); colorless crystals; mp
190–191 °C.
Methyl 5-[(4-Methylphenyl)thiosemicarbazido]-2-phenyl-1,3-
oxazole-4-carboxylate (3d)
Compound 3d was prepared following the general procedure from
2a (2.33 g) and 4-methylphenyl isothiocyanate (1.57 g) in anhyd di-
oxane (20 mL); yield: 3.09 g (81%); colorless crystals; mp 151–
152 °C.
Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C,
56.84; H, 5.02; N, 18.37.
Methyl 5-Hydrazino-2-(4-methylphenyl)-1,3-oxazole-4-carbox-
ylate (2b)
Compound 2b was prepared following the general procedure from
1b (2.88 g) in MeOH (20 mL). The product was purified by recrys-
tallization from MeOH; yield: 2.17 g (88%); colorless crystals; mp
195–196 °C.
Anal. Calcd for C19H18N4O3S: C, 59.67; H, 4.74; N, 14.65; S, 8.38.
Found: C, 59.85; H, 4.99; N, 14.59; S, 8.45.
Alkyl 5-Arylamino-1,3,4-thiadiazol-2-yl(acylamino)acetates
5a–h; General Procedure
To a solution of compound 2a–c (10 mmol) in anhyd dioxane (15
mL) was added the corresponding aryl isothiocyanate (11 mmol).
The mixture was refluxed for 8 h and dioxane was removed in vac-
uo. For crystallization, the residue was treated with H2O; then it was
filtered off and recrystallized from an appropriate solvent (Table 1).
Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N, 17.00. Found: C,
58.40; H, 5.32; N, 17.19.
Ethyl 5-Hydrazino-2-phenyl-1,3-oxazole-4-carboxylate (2c)
Compound 2c was prepared following the general procedure from
1c (2.88 g) in EtOH (30 mL). The product was purified by recrys-
Synthesis 2003, No. 18, 2851–2857 © Thieme Stuttgart · New York

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Synthesis of Derivatives of (1,3,4-Thiadiazol-2-yl)glycine
2855
Methyl 5-Anilino-1,3,4-thiadiazol-2-yl(benzoylamino)acetate
(5a)
Methyl 4-Methylbenzoylamino[5-(4-toluidino)-1,3,4-thiadiazol-
2-yl]acetate (5g)
From 2a: Compound 5a was prepared following the general proce-
dure from 2a (2.33 g) and phenyl isothiocyanate (1.49 g) in anhyd
dioxane. The product was recrystallized from MeOH; yield: 2.6 g
(71%); colorless crystals; mp 181–182 °C.
Compound 5g was prepared following the general procedure from
2b (2.47 g) and 4-methylphenyl isothiocyanate (1.64 g). The prod-
uct was purified by recrystallization from MeOH; yield: 3.29 g
(83%); colorless crystals; mp 207–209 °C.
Anal. Calcd for C18H16N4O3S: C, 58.68; H, 4.38; N, 15.21; S, 8.70.
Found: C, 59.03; H, 4.36; N, 14.99; S, 8.79.
Anal. Calcd for C20H20N4O3S: C, 60.59; H, 5.08; N, 14.13; S, 8.09.
Found: C, 60.67; H, 5.03; N, 14.31; S, 8.03.
From 3a: This compound was also obtained from 3a (3.28 g) by
boiling in dioxane (15 mL) for 8 h. The product was isolated as de-
scribed in the general procedure; yield: 2.53 g (69%); mp 180–
181 °C. The IR spectra for the samples of compound 5a obtained
from 2a and 3a were identical.
Methyl 4-Methylbenzoylamino[5-(4-methoxyanilino)-1,3,4-thi-
adiazol-2-yl]acetate (5h)
Compound 5h was prepared following the general procedure from
2b (2.47 g) and 4-methoxyphenyl isothiocyanate (1.82 g). The
product was purified by recrystallization from dioxane; yield: 3.13
g (76%); pale yellow crystals; mp 207–209 °C.
Methyl 5-Anilino-1,3,4-thiadiazol-2-yl(4-methylbenzoylami-
no)acetate (5b)
Compound 5b was prepared following the general procedure from
2b (2.47 g) and phenyl isothiocyanate (1.49 g). The product was pu-
rified by recrystallization from MeOH; yield: 2.48 g (65%); pale
yellow crystals; mp 201–203 °C.
Anal. Calcd for C20H20N4O4S: C, 58.24; H, 4.89; N, 13.58; S, 7.77.
Found: C, 58.49; H, 5.11; N, 13.77; S, 8.10.
2-Acylaminomethyl-5-arylamino-1,3,4-thiadiazoles 6a,g; Gen-
eral Procedure
A solution of compound 5a,g (10 mmol) in 10% aq NaOH (80 mL)
was heated at 80–90 °C under stirring for 8 h. The mixture was acid-
ified with glacial AcOH to pH ca. 4–5. The precipitate formed was
filtered off and recrystallized from MeOH (Table 1).
Anal. Calcd for C19H18N4O3S: C, 59.67; H, 4.74; N, 14.65; S, 8.38.
Found: C, 59.55; H, 4.98; N, 14.53; S, 8.29.
Ethyl5-Anilino-1,3,4-thiadiazol-2-yl(benzoylamino)acetate(5c)
Compound 5c was prepared following the general procedure from
2c (2.47 g) and phenyl isothiocyanate (1.49 g). The product was pu-
rified by recrystallization from EtOH; yield: 2.78 g (73%); pale yel-
low crystals; mp 213–214 °C.
5-Anilino-2-(benzoylamino)methyl-1,3,4-thiadiazole (6a)
Compound 6a was prepared following the general procedure from
5a (3.67 g). The product was purified by recrystallization from
MeOH; yield: 1.95 g (63%); colorless crystals; mp 221–222 °C.
Anal. Calcd for C19H18N4O3S: C, 59.67; H, 4.74; N, 14.65; S, 8.38.
Found: C, 59.45; H, 4.56; N, 14.56; S, 8.37.
Anal. Calcd for C16H14N4OS: C, 61.92; H, 4.55; N, 18.05; S, 10.33.
Found: C, 62.17; H, 4.61; N, 17.85; S, 10.25.
Methyl Benzoylamino[5-(4-toluidino)-1,3,4-thiadiazol-2-yl]ace-
tate (5d)
From 2a: Compound 5d was prepared following the general proce-
dure from 2a (2.33 g) and 4-methylphenyl isothiocyanate (1.64 g).
The product was purified by recrystallization from benzene; yield:
2.93 g (77%); pale yellow crystals; mp 173–175 °C.
2-(4-Methylbenzoylamino)methyl-5-(4-toluidino)-1,3,4-thiadia-
zole (6g)
Compound 6g was prepared following the general procedure from
5g (3.96 g). The product was purified by recrystallization from
MeOH; yield: 2.16 g (65%); colorless crystals; mp 249–250 °C.
Anal. Calcd for C18H18N4OS: C, 63.88; H, 5.36; N, 16.55; S, 9.47.
Found: C, 64.07; H, 5.53; N, 16.64; S, 9.39.
Anal. Calcd for C19H18N4O3S: C, 59.67; H, 4.74; N, 14.65; S, 8.38.
Found: C, 59.52; H, 4.87; N, 14.88; S, 8.53.
From 3d: This compound was also obtained from 3d (3.82 g) by
boiling in dioxane (15 mL) for 8 h. The product was isolated as de-
scribed in the general procedure; yield: 3.01 g (79%).
Dialkyl 2-Aryl(styryl)-5-hydrazino-1,3-oxazol-4-ylphospho-
nates 9a–e; General Procedure
To a solution of compound 8a–e (10 mmol) in THF (15 mL) was
added hydrazine hydrate (45 mmol) and the mixture was stirred at
20–25 °C for 72 h. Then the solvent was removed in vacuo and the
residue was treated with H2O. Compounds 9a–d were purified by
crystallization; compound 9e was extracted from aq emulsion with
CH2Cl2 (3 × 20 mL), dried (Na2SO4), and freed of the solvent in
vacuo to give a thick oily substance which was used further without
additional purification (Table 1).
Methyl Benzoylamino[5-(4-methoxyanilino)-1,3,4-thiadiazol-2-
yl]acetate (5e)
Compound 5e was prepared following the general procedure from
2a (2.33 g) and 4-methoxyphenyl isothiocyanate (1.82 g). The prod-
uct was purified by recrystallization from MeOH; yield: 3.02 g
(76%), colorless crystals; mp 191–192 °C.
Anal. Calcd for C19H18N4O4S: C, 57.28; H, 4.55; N, 14.06; S, 8.05.
Found: C, 59.53; H, 4.62; N, 14.17; S, 7.89.
Dimethyl 5-Hydrazino-2-phenyl-1,3-oxazol-4-ylphosphonate
(9a)
Compound 9a was prepared as described before.16
Ethyl Benzoylamino[5-(4-toluidino)-1,3,4-thiadiazol-2-yl]ace-
tate (5f)
Compound 5f was prepared following the general procedure from
2c (2.47 g) and 4-methylphenyl isothiocyanate (1.64 g). The prod-
uct was purified by recrystallization from EtOH; yield: 3.09 g
(78%); pale yellow crystals; mp 193–194 °C.
Dimethyl 5-Hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-
ylphosphonate (9b)
Compound 9b was prepared following the general procedure from
8b (3.74 g). The product was purified by recrystallization from aq
EtOH; yield: 2.58 g (87%); colorless crystals; mp 120–121 °C.
Anal. Calcd for C20H20N4O3S: C, 60.59; H, 5.08; N, 14.13; S, 8.09.
Found: C, 60.72; H, 5.15; N, 14.03; S, 8.23.
Anal. Calcd for C12H16N3O4P: C, 48.49; H, 5.43; N, 14.14; P, 10.42.
Found: C, 48.56; H, 5.58; N, 13.86; P, 10.12.
Synthesis 2003, No. 18, 2851–2857 © Thieme Stuttgart · New York

2856
A. V. Golovchenko et al.
PAPER
Dimethyl 5-Hydrazino-2-styryl-1,3-oxazol-4-ylphosphonate
(9c)
Diethyl 5-(Anilino-1,3,4-thiadiazol-2-yl)(cinnamoylamino)me-
thylphosphonate (10e)
Compound 10e was prepared following the general procedure from
9e (3.37 g) and phenyl isothiocyanate (1.49 g). The product was pu-
rified by recrystallization from EtOH; yield: 3.63 g (77%); pale yel-
low crystals; mp 171–173 °C.
Compound 9c was prepared as described before.16
Diethyl 5-Hydrazino-2-phenyl-1,3-oxazol-4-ylphosphonate (9d)
Compound 9d was prepared following the general procedure from
8d (3.88 g). After evaporating the solvent in vacuo, the residue was
treated with hexane, filtered off, and recrystallized from benzene;
yield: 2.6 g (84%); colorless crystals; mp 78–80 °C.
Anal. Calcd for C22H25N4O4PS: C, 55.92; H, 5.33; N, 11.86; P, 6.56;
S, 6.79. Found: C, 56.10; H, 5.58; N, 11.74; P, 6.42; S, 6.60.
Anal. Calcd for C13H18N3O4P: C, 50.16; H, 5.83; N, 13.50; P, 9.95.
Found: C, 50.33; H, 6.02; N, 13.45; P, 9.91.
Dimethyl (4-Methylbenzoylamino)[5-(4-toluidino)-1,3,4-thiadi-
azol-2-yl]methylphosphonate (10f)
Compound 10f was prepared following the general procedure from
9b (2.97 g) and 4-methylphenyl isothiocyanate (1.64 g). The prod-
uct was purified by recrystallization from MeOH; yield: 2.91 g
(65%); colorless crystals; mp 130–132 °C.
Diethyl 5-Hydrazino-2-styryl-1,3-oxazol-4-ylphosphonate (9e)
Compound 9e was prepared following the general procedure from
8e (4.14 g); yield: 3.13 g (93%); pale yellow oil which was used
without purification in the preparation of 10e.
Anal. Calcd for C20H23N4O4PS: C, 53.81; H, 5.19; N, 12.55; P, 6.94;
S, 7.18. Found: C, 53.97; H, 4.91; N, 12.45; P, 6.82; S, 7.03.
Anal. Calcd for C15H20N3O4P: C, 53.41; H, 5.98; N, 12.46; P, 9.18.
Found: C, 53.62; H, 6.13; N, 12.45; P, 9.31.
X-Ray Structure Determination of 5d
Dialkyl 5-(Arylamino-1,3,4-thiadiazol-2-yl)(acylamino)meth-
ylphosphonates 10a–f; General Procedure
A solution of compound 9a–e (10 mmol) and aryl isothiocyanate
(11 mmol) in dioxane (10 mL) was boiled for 12 h. The precipitate
formed was filtered off, dried in vacuo, and recrystallized from
MeOH or EtOH (Table 1).
Crystal Data: C19H18N4O3S, M = 382.44, monoclinic, a = 9.747(3),
b = 20.078(7), c = 9.931(2) Å, = 100.85(3), V = 1908.8 Å3, Z = 4,
d = 1.331 gcm–3, space group P21/c, = 1.87 cm–1, F(000) = 800.6,
sphere with d = 0.36 mm.
Data Collection: All crystallographic measurements were per-
formed at 20 °C on a CAD-4 Enraf-Nonius diffractometer operating
in the -2 scan mode (the ratio of the scanning rates /2 = 1.2).
Intensity data were collected within the range 2 < < 25° , (0 < h <
11, 0 < k < 23, –11 < l < 11) using graphite-monochromated Mo-K
radiation ( = 0.71069 Å). Intensities of 3674 reflections (3341
unique reflections, Rint = 0.033) were measured. Data were correct-
ed for Lorentz and polarization effects, and an empirical absorption
correction based on azimuthal scan data was applied.23
Dimethyl 5-(Anilino-1,3,4-thiadiazol-2-yl)(benzoylamino)meth-
ylphosphonate (10a)
Compound 10a was prepared following the general procedure from
9a (2.83 g) and phenyl isothiocyanate (1.49 g). The product was
purified by recrystallization from MeOH; yield: 3.3 g (79%); color-
less crystals; mp 194–195 °C.
Anal. Calcd for C18H19N4O4PS: C, 51.67; H, 4.58; N, 13.39; P, 7.40;
S, 7.66. Found: C, 51.83; H, 4.61; N, 13.31; P, 7.40; S, 7.66.
Structure Solution and Refinement: The structure was solved by di-
rect methods and refined by full-matrix least-squares technique in
the anisotropic approximation using the CRYSTALS program
package.24 In the refinement 1655 reflections with I >3 (I) were
used.
Dimethyl 5-(Anilino-1,3,4-thiadiazol-2-yl)(4-methylbenzoyl-
amino)methylphosphonate (10b)
Compound 10b was prepared following the general procedure from
9b (2.97 g) and phenyl isothiocyanate (1.49 g). The product was pu-
rified by recrystallization from MeOH; yield: 3.07 g (71%); color-
less crystals; mp 133–135 °C.
All hydrogen atoms were located in the difference Fourier maps and
included in the final refinements with fixed positional and thermal
parameters [only H (3) and H(4) atoms participating in hydrogen
bonding were refined isotropically]. Convergence was obtained at
R1 = 0.053 and wR2 = 0.053, GOF = 1.162 (252 refined parame-
ters; obs/variabl. = 6.6; the largest and minimal peaks in the final
difference map, 0.33 and –0.27 eÅ–3). Chebyshev weighting
scheme25 with the parameters 1.26, 0.82, and 1.00 was used.26
Anal. Calcd for C19H21N4O4PS: C, 52.77; H, 4.89; N, 12.96; P, 7.16;
S, 7.41. Found: C, 52.58; H, 5.08; N, 12.79; P, 7.05; S, 7.31.
Dimethyl 5-(Anilino-1,3,4-thiadiazol-2-yl)(cinnamoylami-
no)methylphosphonate (10c)
Compound 10c was prepared following the general procedure from
9c (3.09 g) and phenyl isothiocyanate (1.49 g). The product was pu-
rified by recrystallization from MeOH; yield: 3.34 g (75%); pale
yellow crystals; mp 160–161 °C.
References
(1) Adlington, R. M.; Baldwin, J. E.; Catteric, D.; Pritchard, G.
J. J. Chem. Soc., Perkin Trans. 1 1999, 855.
(2) Adlington, R. M.; Baldwin, J. E.; Catteric, D.; Pritchard, G.
J. J. Chem. Soc., Perkin Trans. 1 2000, 299.
Anal. Calcd for C20H21N4O4PS: C, 54.05; H, 4.76; N, 12.61; P, 6.97;
S, 7.21. Found: C, 54.15; H, 4.58; N, 12.52; P, 6.86; S, 7.10.
(3) Jones, R. C. F.; Berthelot, D. J. C.; Iley, J. N. Chem.
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(4) Adlington, R. M.; Baldwin, J. E.; Catteric, D.; Pritchard, G.
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Diethyl 5-(Anilino-1,3,4-thiadiazol-2-yl)(benzoylamino)meth-
ylphosphonate (10d)
Compound 10d was prepared following the general procedure from
9d (3.11 g) and phenyl isothiocyanate (1.49 g). The product was pu-
rified by recrystallization from EtOH; yield: 3.48 g (78%); pale yel-
low crystals; mp 186–187 °C.
Anal. Calcd for C20H23N4O4PS: C, 53.81; H, 5.19; N, 12.55; P, 6.94;
S, 7.18. Found: C, 54.11; H, 5.43; N, 12.43; P, 6.83; S, 7.09.
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Synthesis 2003, No. 18, 2851–2857 © Thieme Stuttgart · New York

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Synthesis of Derivatives of (1,3,4-Thiadiazol-2-yl)glycine
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Synthesis 2003, No. 18, 2851–2857 © Thieme Stuttgart · New York