A convenient approach to synthesis of benzoxazol-2-ylglycine and benzothiazol-2-ylglycicne derivatives

Full text of DOI:10.1134/S1070363213060364

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 6, pp. 1180–1182. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © E.I. Lukashuk, K.M. Kondratyuk, V.M. Prokopenko, A.V. Golovchenko, V.S. Brovarets, 2013, published in Zhurnal Obshchei
Khimii, 2013, Vol. 83, No. 6, pp. 1050–1052.
LETTERS
TO THE EDITOR
A Convenient Approach to Synthesis
of Benzoxazol-2-ylglycine
and Benzothiazol-2-ylglycicne Derivatives
E. I. Lukashuk, K. M. Kondratyuk, V. M. Prokopenko,
A. V. Golovchenko, and V. S. Brovarets
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kyiv, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received January 16, 2013
DOI: 10.1134/S1070363213060364
Introduction of pharmacophore heterocyclic
moieties into the peptide chain is of particular interest
because it results in a promising new bioregulators [1]
with a significant anticonvulsant, neuropathic and
analgesic activity [2–6], and also oxytocin antagonists
[7]. However, the functionalization of α-amino acids
with electron-acceptor heterocycles is a challenging
task, due to their ease of decarboxylation. This
substantially limits the use of such amino acids in
peptide synthesis.
In this work, we developed a convenient approach
to the synthesis of glycine derivatives, which were
modified at the α-position with benzoxazol-2-yl and
benzothiazol-2-yl moieties. For the first time we used
for this purpose available 2-phenyl-4-dichloro-
methylene-5(4H)-oxazolone [8], which was involved
into the reactions sequence: I → III → V or VII. The
reaction I → III has been previously described by an
example of 2-aminothiophenol [9], and all the other
reaction were investigated by us for the first time. The
O
Ph
Ph
Cl
H2N
HX
O
+
H
N
NH
NH
N
H2NCH2Ph
Ph
Cl
O
O
N
X
IIа, IIb
I
THF
O
O
Et3N
X
NH
NH
Ph
Ph
H
N
O
IVа, IVb
Vа, Vb
DMF
O
Δ
EtO
EtO
OEt
OEt
O
N
X
Ph
P
O
P
IIIа, IIIb
H2NCH2P(O)(OEt)2
X = O
H
N
NH
NH
O
O
N
O
O
O
O
NH
NH
VII
Ph
Ph
VI
X = O (IIа–Vа), S (IIb–Vb).
1180

A CONVENIENT APPROACH TO SYNTHESIS OF BENZOXAZOL-2-YLGLYCINE
1181
final step in this process is the cleavage of oxazolones
III with benzylamine or diethyl aminomethylphos-
phonate to form intermediates IV and VI followed by
prototropic isomerization into the products V and VII.
IIIa in 40 ml of dioxane was added 0.23 g (0.0021 mol)
of benzylamine. The mixture was heated at 65–70°C
for 5 h (TLC monitoring) and evaporated in a vacuum
to dryness. The residue was purified by recrystalliza-
tion from benzene. Yield 80%, mp 162–163°С. IR
spectrum, ν, cm–1: 1690 (С=О), 1640 (С=О), 3310 (N–H).
Compound VII is of particular interest since it
belongs to the class of phosphonopeptide mimetics
[10, 11].
3
1Н NMR spectrum, δ,ppm: 4.43 d (2Н, CH2, JHH 5.2
Hz), 6.13 d (1Н, СН, 3JHH 7.0 Hz), 7.25–8.00 m (14Н,
2С6Н5, С6Н4), 9.03 br. s (1Н, NH), 9.46 d (1Н, NH,
3JHH 7.0 Hz). Mass spectrum, m/z: 386 [M + 1]+.
Found, %: С 71.36; Н 4.82; N 10.98. C23H19N3O3.
Calculated, %: С 71.67; Н 4.97; N 10.90.
The assumed structures of the new compounds are
1
in a good agreement with the data of H NMR and IR
spectroscopy. Thus, in the IR spectrum of compound
IIIa there are two intensive absorption bands at 1713
and 1655 cm–1 belonging to the stretching vibration of
N-(Benzothiazol-2-ylbenzylcarbamoylmethyl)benz-
amide (Vb) was prepared similarly from oxazolone
IIIb. Yield 82%, mp 184–185°С. IR spectrum, ν, cm–1:
1633 (С=О, shoulder), 3277 (NH). 1Н NMR spectrum,
1
the bonds C=O and C=N of oxazolone ring. The H
NMR spectra of products V and VII contain
characteristic two doublet signals of the protons of
NH–CH group at 6.13–6.23 and 9.42–9.46 ppm
3
δ, ppm: 4.31–4.54 m (2Н, CH2), 6.23 d (1Н, СН, JHH
It should be noted that attempts to obtain such
structure with benzothiazol-2-yl moiety have been
made earlier, but the target compound was not isolated
in a pure form [12–14]. Only dipeptides containing
quinolin-2-yl, pyridin-2-yl, and 4-pyrimidin-2-yl
moieties in the peptide chain have been synthesized
[15].
7.2 Hz), 7.26–8.11 m (14Н, 2С6Н5, С6Н4), 9.08 br. s
(1Н, NH), 9.45 br. s (1Н, NH). Mass spectrum, m/z:
402 [M + 1]+. Found, %: С 68.56; Н 4.62; N 10.65; S
7.89. C23H19N3O2S. Calculated, %: С 68.81; Н 4.77; N
10.47; S 7.99.
Diethyl
[(2-benzoxazol-2-yl)-2-benzoylamino-
acetylamino)methyl]phosphonate (VII). To a solu-
tion of 0.002 mol of compound IIIa in 40 ml of
dioxane was added 0.34 g (0.0021 mol) of the freshly
prepared aminomethylphosphonic acid diethyl ester
[16]. The mixture was heated at 65–70°C for 6 h (TLC
monitoring). The solvent was evaporated in a vacuum,
and the residue was purified by recrystallization from
acetonitrile. Yield 88%, mp 134–135°С. IR spectrum,
ν, cm–1: 962 (Р–ОСС), 1027 (РОС), 1211 (Р=О), 1650
Thus, we have developed a new convenient method
for the synthesis of benzoxazol-2-yl- and benzothiazol-
2-ylglycine derivatives, which was applied to obtain a
phosphonopeptide mimetic containing benzoxazol-2-yl
moiety in the side chain.
2-Phenyl-4-(2,3-dihydrobenzo[1,3]oxzol-2-ylidene)-
1,3-oxazol-5-one (IIIа). To a suspension of 0.008 mol
of compound I in 40 ml of tetrahydrofuran under
cooling with ice water and stirring was added 1.7 g
(0.017 mol) of triethylamine and a solution of 0.5 g
(0.004 mol) of 2-aminophenol in 50 ml of tetra-
hydrofuran within 1 h. The mixture was stirred for 4 h
and kept for 24 h at 20–25°C. The precipitate was
filtered off, and the filtrate was evaporated in a
vacuum to dryness. The residue was purified by
recrystallization from acetonitrile. Yield 70%, mp
259–261°С. IR spec-trum, ν, cm–1: 1655 (С=N), 1713
(С=О), 3228 (NH). Mass spectrum, m/z: 279 [M + 1]+.
Found, %: С 69.17; Н 3.48; N 10.14. C16H10N2O3.
Calculated, %: С 69.06; Н 3.62; N 10.07.
1
(С=О, shoulder), 3230 (NH). Н NMR spectrum, δ,
ppm: 1.17–1.21 m (6Н, 2ОСН2СН3), 3.66–3.77 m
(2Н, СН2), 3.99–4.06 m (4Н, ОСН2СН3), 6.18 d (1Н,
СН, 3JHH 8.0 Hz), 7.43–7.97 m (9Н, С6Н5, С6Н4), 8.98
t (1Н, NH, 3JHH 5.0 Hz), 9.42 d (1Н, NH, 3JHH 8.0 Hz).
31Р NMR spectrum: δр 22.9 ppm. Mass spectrum, m/z:
446 [M + 1]+. Found, %: С 56.39; Н 5.36; N 9.57; Р
6.81. C21H24N3O6Р. Calculated, %: С 56.63; Н 5.43; N
9.43; Р 6.95.
The IR spectra were recorded on a Vertex 70
instrument from KBr pellets. The NMR spectra were
obtained on a Bruker AVANCE DRX-500 spectro-
meter operating at 500.07 (1H) and 202.43 MHz (31P)
and using DMSO-d6 as a solvent; chemical shifts are
reported relative to internal reference TMS or external
reference 85% phosphoric acid. GC-MS spectra were
recorded on a liquid chromatograph-mass spectrometer
system HPLC Agilent 1100 Series equipped with a
2-Phenyl-4-(2,3-dihydrobenzo[1,3]thiazol-2-ylidene)-
1,3-oxazol-5-one (IIIb) was obtained by the described
method [9].
N-(Benzoxazol-2-ylbenzylcarbamoylmethyl)benz-
amide (Va). To a solution of 0.002 mol of compound
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 6 2013

1182
LUKASHUK et al.
Davies, D., Edwards, R., Exall, A., Hamlett, Ch., Irving, W.,
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diode array with a mass selective detector Agilent
LC\MSD SL [column Zorbax SB-C18 (1.8 µm 4.6 ×
15 mm, PN 821975-932); acetonitrile–water (95:5)
with the addition of 0.1% trifluoroacetic acid (A) or
0.1% aqueous trifluoroacetic acid (B), eluent flow
3 ml min–1, injection volume 1 µL; UV detecting at
215, 254, 265 nm; chemical ionization at atmospheric
pressure (APCI), scan range m/z 80–1000. Melting
points were measured on a Fisher-Johns instrument.
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