Synthesis of C-heteryl-substituted aminomethylphosphonic acids derivatives

Article abstract of DOI:10.1134/S1070363210040067

The available diethyl 5-hydrazino-2-p-tolyl-1,3-oxazol-1-ylphosphonate was readily acylated with chlorides of carboxylic acids of heterocyclic series. On heating in acetic acid it underwent the oxazole ring cleavage, recyclization and diethylation that wa

Full text of DOI:10.1134/S1070363210040067

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 723–727. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.V. Golovchenko, R.N. Solomyannyi, V.S. Brovarets, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4, pp. 563–
567.
Synthesis of C-Heteryl-Substituted Aminomethylphosphonic
Acids Derivatives
A. V. Golovchenko, R. N. Solomyannyi, and V. S. Brovarets
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Murmanskaya ul. 1, Kiev-94, 02660 Ukraine
fax: 38(044)573-2555
e-mail: brovarets@bpci.kiev.ua
Received June 4, 2009
Abstract―The available diethyl 5-hydrazino-2-p-tolyl-1,3-oxazol-1-ylphosphonate was readily acylated with
chlorides of carboxylic acids of heterocyclic series. On heating in acetic acid it underwent the oxazole ring
cleavage, recyclization and diethylation that was used to prepar the substituted 2-p-toluylaminomethyl-
phosphonic acids containing a series of 2-heteryl-1,3,4-oxadiazol-5-yl residues in the α-position relative to the
phosponyl group.
DOI: 10.1134/S1070363210040067
Aminophosphonic acids as analogs of natural
aminocarboxylic acids are of great interest due to their
use or possible use in various fields of medicine and
agriculture. They are analogs of antibiotics, inhibitor
of different enzymes, antiviral preparations, and also
precursors for synthesis of phosphonopeptides [1].
Aminoalkylphosphonic acids containing heterocyclic
residues in the α-position to phosphonic group are less
studied, but approaches to their synthesis and they
properties are very interesting [2]. The С-heteryl-
substituted aminomethylphosphonates and the cor-
responding aminomethylphosphonic acids containing
furan [3–5], thiophene [2, 4, 5], pyrrole [2, 5],
imidazole [6], pyridine [7, 8], and also 1,3,4-oxa- and
1,3,4-thiadiazole fragments [9–11] are known.
coumarin, chromone, and 6-methylchromone frag-
ments (Table 1).
To incorporate the other heterocyclic substituents
into the desired position of the oxadiazole ring we used
precursors ІІІe, IIIf containing chromone system. The
heating of their alcohol solutions with excess of
hydrazine-hydrate results in two recyclization to give
not only 1,3,4-oxadiazole fragment, but pyrazole ring
too. From the two possible transformations
III→V→VII and III→VI→VII some preference is
given to the second. The subsequent heating of
substrates VII in acetic acid results in phosphonic
acids VIIIа and VIIIb. The structures of compounds
represented on the scheme are reliably proved by the
spectral data (Table 2). Thus, the presence of PCHNH
fragment in the recyclization products IV, VII, and
VIII is in agreement with the assignment of signals at
This work concerns the synthesis of 1,3,4-
oxadiazol-2-yl-(amino)methylphosphonic acids con-
taining additional heterocyclic fragments in the azole
ring. To this end we used the known transformation
І→ІІ [11], and then oxazole substrate ІІ was treated
with chlorides of carboxylic acids of heterocyclic
series in the presence of N,N-dimethylaniline. As a
result the new oxazole substrates IIIa–IIIf formed. On
heating in acetic acid the latter undergo recyclization
and ester bonds rupture that led to the formation of the
corresponding phosphonic acids IVа–IVf, substrates
of 1,3,4-oxadiazole series containing in this azole ring
the additional furan, thiophene, 5-phenyl-1,2-oxazole,
1
δH 5.73–6.15 and 8.67–9.55 ppm in the Н NMR
spectra [9–11]. The chromone ring opening III→VII
is attested by the disappearance of an absorption bands
at 1705–1709 cm–1 in the IR spectrum and also by the
presence of singlet signals of N–H fragment of the
pyrazole ring at δH 10.03–10.15 ppm and of OH-group
1
of aryl ring at δH 13.42–13.51 ppm in the H NMR
spectra of compounds VII.
In conclusion we note that compounds IV, VII, and
VIII are promising for the testing as bioregulators of
different actions (cf. [1, 8, 12–15]).
723

724
GOLOVCHENKO et al.
P(O)(OEt)2
H
P(O)(OEt)2
N
N
H2N_NH2·H2O
NH2
Ti
Cl
Ti
N
H
O
O Cl
I
II
HtC(O)Cl/PhNMe2
H
P(O)(OEt)2
Ti
N
P(O)(OH)2
N
H
N
AcOH
Ht
O
Ti
N
Δ
O
N
O
H
O
N
IIIa_IIIf
IVa_IVf
Ht
O
EtOH,
H2N_NH2·H2O,
R
Ht =
Δ
O
O
O
O
H
P(O)(OEt)2
H
P(O)(OEt)2
R
Ti
N
R
N
H
N
O
N
N
Ti
N
X
X
O
H
OH
O
O
VI
V
H2N_NH2·H2O,
H2N_NH2·H2O, Δ
Δ
H
H
Ti
N
P(O)(OH)2
O
Ti
N
P(O)(OEt)2
O
O
O
N
N
AcOH
N
N
R
R
Δ
N
N
H
N
N
H
HO
HO
VIIIa, VIIIb
VIIa, VIIb
O
(a),
N (c),
(b),
(d),
(e),
III, IV:
Ht =
Ph
O
O
S
O
O
O
O
Me
(f); VII, VIII: R = H (a), Me (b).
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

725
SYNTHESIS OF C-HETERYL-SUBSTITUTED
Table 1. Yields, constants, and elemental analysis data for compounds III, IV, VII, and VIII
Found, %
Calculated, %
N P
Comp.
no.
Yield, %
Melting point, °С
Formula
N
P
72
81
87
91
53
59
69
47
77
86
72
74
63
71
71
76
171–173 (EtOH)
160–162 (EtOH)
172–173 (EtOH)
170–172 (EtOH)
168–170 (EtOH)
183–185 (EtOH)
229–231 (AcOH)
228–230 (AcOH)
230–231 (AcOH)
163–165 (AcOH)
181–183 (AcOH)
183–185 (AcOH)
223–225 (EtOH)
225–227 (EtOH)
254–256 (AcOH)
255–257 (AcOH)
10.02
9.65
7.39
7.11
6.24
6.23
6.23
6.06
8.53
8.17
7.03
7.02
7.02
6.80
6.06
5.89
6.80
6.60
C19H22N3O6P
C19H22N3O5PS
C24H25N4O6P
C24H24N3O7P
C24H24N3O7P
C25H26N3O7P
C15H14N3O6P
C15H14N3O5PS
C20H17N4O6P
C20H16N3O7P
C20H16N3O7P
C21H18N3O7P
C24H26N5O6P
C25H28N5O6P
C20H18N5O6P
C21H18N5O6P
10.13
9.73
7.43
7.08
6.32
6.21
6.19
6.01
8.47
8.19
7.01
6.97
6.99
6.73
6.09
5.81
6.72
6.51
IIIа
IIIb
IIIc
IIId
IIIe
IIIf
11.29
8.45
11.37
8.54
8.45
8.49
8.22
8.31
11.57
11.08
12.72
9.52
11.52
11.10
12.84
9.59
IVа
IVb
IVc
IVd
IVe
9.52
9.61
9.23
9.32
IVf
13.69
13.33
15.38
14.92
13.78
13.46
15.49
15.04
VIIа
VIIb
VIIIа
VIIIb
and water, dried over P2O5 in a vacuum desiccator and
recrystallized from a suitable solvent.
EXPERIMENTAL
The IR spectra were recorded on a Vertex 70
О,О-Diethyl {5-[5-(2-hydroxyphenyl)-1Н-pyrazol-
3-yl]-1,3,4-oxa-diazol-2-yl}[(4-methylbenzoyl)amino]-
methylphosphonate (VIIа). A mixture of 0.01 mol of
ІІІe and 0.05 mol of hydrazine hydrate in 5 ml of
ethanol was refluxed for 2 h and kept for 12 h at 20–
25°С. The precipitate was filtered off, washed with
ethanol and water, dried, and recrystallized.
spectrometer from KBr pellets. The Н and 31Р NMR
1
spectra were obtained on
a Varian VXR-300
instrument at 300 and 81 MHz respectively in DMSO-
d6 relative to TMS. The melting points were measured
on a Fisher-Johns instrument.
О,О-Diethyl
5-(2-acylhydrazino)-2-(4-methyl-
phenyl)-1,3-oxazol-4-ylphosphonates (ІІІа–IIIf). To
a solution of 0.01 mol of ІІ in 10 ml of anhydrous
acetonitrile were added 0.011 mol of N,N-di-
methylaniline and 0.0105 mol of a chloride of the
corresponding heterocyclic acid. The mixture was
heated to boiling and kept for 12 h at 20–25°С. The
solvent was removed in a vacuum, and the oily residue
was worked up with water to crystallize. The
precipitate was filtered off, dried, and recrystallized
from a suitable solvent.
О,О-Diethyl {5-[5-(2-hydroxy-5-methylphenyl)-
1Н-pyrazol-3-yl]-1,3,4-oxadiazol-2-yl}[(4-methyl-
benzoyl)amino]methylphosphonate (VIIb) was
prepared similarly from hydrazide ІІІе.
{5-[5-(2-Hydroxyphenyl)-1Н-pyrazol-3-yl]-1,3,4-
oxadiazol-2-yl}[(4-methylbenzoyl)-amino]methylphos-
phonate (VIIIа). A solution of 0.01 mol of VIIа in 10 ml
of acetic acid was refluxed for 6 h. The mixture was kept
for 12 h at 20–25°С. The precipitate was filtered off,
washed with ethanol and water, dried, and recrystallized.
5-Heteryl-1,3,4-oxadiazol-2-yl(4-methylbenzoyl-
amino)methylphosponic acids (IVа–IVf). A mixture
of 0.01 mol of ІІІа–IIIf in 3 ml of the glacial acetic
acid was refluxed for 6 h and kept for 12 h at 20–25°С.
The precipitate was filtered off, washed with ethanol
{5-[5-(2-Hydroxy-5-methylphenyl)-1Н-pyrazol-
3-yl]-1,3,4-oxadiazol-2-yl}[(4-methyl-benzoyl)amino]-
methylphosphonate (VIIIb) was prepared similarly
from VIIb.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

726
GOLOVCHENKO et al.
Table 2. The spectral data for compounds IV, VII, VIII
Comp.
no.
31Р NMR spectrum,
δ, ppm (DMSO-d6)
1Н NMR spectrum, δ, ppm (DMSO-d6)
IR spectrum (KBr), ν, cm–1
12.22
12.11
12.04
12.20
1225 (P=O), 1659 (C=O),
2981–3261 (NH as.)
IIIа
1.29 t (6H, 2CH3), 2.35 s (3H,CH3), 4.09 m (4Н, СН2О), 6.62–7.84 m (7Н,
С6Н4, 3H furan), 8.39 s (1Н, NH), 10.65 s (1H, NH)
1219 (P=O), 1641 (C=O),
2986–3320 (NH as.)
IIIb
1.29 t (6H, 2CH3), 2.35 s (3H,CH3), 4.09 m (4Н, 2 СН2О), 7.17–7.90 m (7Н,
С6Н4, 2H, thiophen), 8.47 s (1Н, NH), 10.80 s (1H, NH)
1240 (P=O), 1693 (C=O),
2983–3275 (NH as.)
IIIc
1.30 t (6H, 2CH3), 2.35 s (3H,CH3), 4.10 m (4Н, СН2О), 7.25–7.96 m (9Н,
С6Н4, С6Н5), 8.65 s (1Н, NH), 11.14 s (1Н, NH)
1238 (P=O), 1683 (C=O),
1716 (C=O), 2911–3322 (NH
as.)
IIId
1.28 t (6H, 2CH3), 2.35 s (3H,CH3), 4.07 m (4Н, 2 СН2О), 7.25–7.95 m (8Н,
С6Н4, 4Н, coumarin), 8.63 br.s (1Н, NH), 8.89 s (1Н, С4–Н, coumarin),
10.45 s (1Н, NH)
1.31 t (6H, 2CH3), 2.36 s (3H,CH3), 4.11 m (4Н, 2 СН2О), 6.89 s (1Н, С3–Н,
chromone), 7.23–8.08 m (8Н, С6Н4, 4Н, chromone), 8.74 s (1Н, NH), 11.45 s
(1Н, NH)
12.30
12.10
12.20
11.73
8.50
1240 (P=O), 1640 (C=O),
1705 (C=O), 2987–3207 (NH
as.)
IIIe
1236 (P=O), 1638 (C=O),
1709 (C=O), 2986–3235 (NH
as.)
IIIf
1.30 t (6H, 2CH3), 2.35 s (3H,CH3), 2.48 s (3H,CH3), 4.11 m (4Н, 2ОСН2),
6.86 s (1Н, С3–Н, chromone), 7.25–7.85 m (7Н, С6Н4, 3Н, chromone), 8.73 s
(1Н, NH), 11.42 s (1Н, NH)
1222 (Р=О), 1642а (С=О),
2608–3260 (NH, ОН as.)
3
IVа
2.39
s
(3H,CH3), 4.84 br.s (ОН+Н2О), 5.73 d.d (1Н, СН, JHH
8.7 Hz, 2JHР 21.6 Hz), 6.72–7.97 m (7Н, С6Н4, 3Н, furan), 8.77 d.d (1Н, NH,
3JHH 8.9 Hz, 3JHР 3.3 Hz)
3
2
1212 (Р=О), 1643 (С=О),
2671–3262 (NH, ОН as.)
IVb
IVc
IVd
IVe
IVf
2.38 s (3Н, CH3), 5.0 br.s (ОН+Н2О), 5.76 d.d (1Н, СН, JHH 8.4 Hz, JHР
3
21.9 Hz), 7.25–7.90 m (7Н, С6Н4, 3Н, thiophen), 8.81 d.d (1Н, NH JHH 8.4
Hz, 3JHР 3.3 Hz)
2.38 s (3Н, CH3), 5.85 d.d (1Н, СН, 3JHH 8.6 Hz, 2JHР 21.6 Hz), 7.26–8.02 m
(9Н, С6Н4, С6Н5), 8.95 d.d (1Н, NH, 3JHH 8.6 Hz, 3JHР 3.8 Hz)
1225 (Р=О), 1644 (С=О),
2914–3257 (NH, ОН as.)
11.70
12.01
11.98
1240а (P=O), 1626а (C=O),
1747а (C=O), 2689–3250
(NH, ОН as.)
2.38 s (3Н, CH3), 5.80 d.d (1Н, СН, 3JHH 8.7 Hz, 2JHР 21.3 Hz), 7.26–7.94 m
(8Н, С6Н4, 4Н, coumarin), 8.77 d.d (1Н, NH, 3JHH 8.7 Hz, 3JHР 3.6 Hz), 8.84 s
(1Н, С4–Н, coumarin)
3
2
1299 (P=O), 1632 (C=O),
1702 (C=O), 2990–3215
(NH, ОН as.)
2.38 s (3Н, CH3), 3.95 br.s (ОН+Н2О), 5.79 d.d (1Н, СН, JHH 8.5 Hz, JHР
21.2 Hz), 6.90 s (1Н, С3–Н, chromone), 7.29–8.00 m (8Н, С6Н4, 4Н, chro-
mone), 8.75 d.d (1Н, NH, 3JHH 8.7 Hz, 3JHР 3.2 Hz)
1236 (P=O), 1638 (C=O),
1697 (C=O), 2987–3197 (NH,
ОН as.)
2.39 s (3Н, CH3), 2.48 s (3Н, CH3), 3.90 br.s (ОН+Н2О), 5.82 d.d (1Н, СН,
2
3JHH 8.6 Hz, JHР 21.9 Hz), 7.08 s (1Н, С3–Н, chromone), 7.25–7.87 m (7Н,
С6Н4, 3Н, chromone), 8.88 d.d (1Н, NH, 3JHH 8.6 Hz, 3JHР 3.3 Hz)
10.66
11.39
1239a (P=O), 1651 (C=O),
2990–3298 (NH, ОН as.)
VIIа
1.24 t (6Н, 2CH3), 2.37 s (3Н, CH3), 4.18 m (4Н, 2CH2О), 6.17 d.d (1Н, СН,
2
3JHH 8.9 Hz, JHР 21.0 Hz), 6.90–7.85 m (9Н, 2С6Н4, С4–Н, pyrazole), 9.63
d.d (1Н, NH, 3JHH 8.9 Hz, 3JHР 3.7 Hz), 10.15 s (1Н, NH), 13.42 s (1Н, ОН)
1256a (P=O), 1650 (C=O),
2982–3253 (NH, ОН as.)
VIIb
1.27 t (6Н, 2CH3), 2.27 s (3Н, CH3), 2.40 s (3Н, CH3), 4.19 m (4Н, 2СН2О),
6.15 d.d (1Н, СН, 3JHH 9.0 Hz, 2JHР 22.2 Hz), 6.88–7.88 m (7Н, С6Н4, С6Н3),
3
3
7.51 s (1Н, С4–Н, pyrazole), 9.55 d.d (1Н, NH, JHH 9.0 Hz, JHР 3.8 Hz),
10.03 s (1Н, NH), 13.51 s (1Н, ОН)
3
2
11.34
11.35
1189a (P=O), 1648a (C=O),
2900–3224 (NH, ОН as.)
VIIIа
2.36 s (3Н, CH3), 3.90 br.s (ОН+Н2О), 5.80 d.d (1Н, СН, JHH 8.9 Hz, JHР
22.0 Hz), 6.92–7.87 m (9Н, 2С6Н4, С4–Н, pyrazole), 8.95 d.d (1Н, NH, JHH
3
8.9 Hz), 10.40 s (1Н, NH)
1189а (P=O), 1648а (C=O),
2977–3203 (NH, ОН as.)
VIIIb
2.28 s (3Н, CH3), 2.39 s (3Н, CH3), 4.0 br.s (ОН+Н2О), 5.73 d.d (1Н, СН,
3JHH 8.8 Hz, 2JHР 21.9 Hz), 6.87–7.86 m (7Н, С6Н4, С6Н3), 7.52 s (1Н, С4–Н,
pyrazole), 8.67 d.d (1Н, NH, 3JHH 8.8 Hz, 3JHР 4.0 Hz), 9.98 s (1Н, NH)
а Band with arm.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

727
SYNTHESIS OF C-HETERYL-SUBSTITUTED
9. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S.,
Chernega, A.A., and Drach, B.S., Synthesis, 2003,
no. 18, p. 2851.
RFERENCES
1. Aminophosphonic and Aminophosphinic Acids, Ku-
khar, V.P. and Hudson, H.R., Eds., Chichester: Wiley,
2000.
2. Hubert, C., Oussaid, B., Etemad–Moghadam, Koening, M.,
and Garrigues, B., Synthesis, 1994, no. 1, p. 51.
3. Lugovkin, B.P., Zh. Obshch. Khim., 1976, vol. 46, no. 3,
p. 555.
4. Demir, A.S., Tanyeli, C., Sesenoghu, O., and Demic, S.,
Tetrahedron Lett., 1996, vol. 37, no. 3, p. 407.
5. Hudson, H.R., Lee, R.J., and Matthews, R.W., Phosph.
Sulfur, Silicon, 2004, vol. 179, p. 1691.
6. Matevosyan, G.L., Matyushicheva, R.M., Vodovato-
va, S.N., and Zavlin, P.M., Zh. Obshch. Khim., 1981,
vol. 51, no. 4, p. 775.
10. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S., and
Drach, B.S., Zh. Obshch. Khim., 2003, vol. 73, no. 11,
p. 1933.
11. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S.,
Chernega, A.A., and Drach, B.S., Zh. Obshch. Khim.,
2005, vol. 75, no. 3, p. 461.
12. Boduszek, B., Phosph. Sulfur, Silicon, 1995, vol. 104,
p. 63.
13. Boduszek, B., Phosph. Sulfur, Silicon, 1996, vol. 113,
p. 209.
14. Cottier, L., Descotes, G., Gonera, G., Grabowski, G.,
Levkowski, J., and Skowronski, R., Phosph. Sulfur,
Silicon, 1996, vol. 118, p. 181.
7. Boduszek, B., Tetrahedron, 1996, vol. 52, no. 38,
p. 12483.
8. Boduszek, B., Phosph. Sulfur, Silicon, 1997, vol. 122,
p. 27.
15. Tournet, M., Cai, D., Larson, R.D., and Reider, P.T.,
Tetrahedron Lett., 1998, no. 39, p. 1717.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010