Steric structure of N-(2-Hydrazono-2-hydroxyethyl)-d-pseudoephedrine and its intramolecular heterocyclization under the action of orthoformic ester

Article abstract of DOI:10.1134/S1070363207090186

An X-ray structural investigation of N-(2-hydrazono-2-hydroxyethyl)-d- pseudoephedrine is performed, and intramolecular heterocyclization of this compound with orthoformic ester is studied. The final reaction product is found to be a compound containing a morpholone ring rather than substituted 1,3,4-oxadiazole.

Full text of DOI:10.1134/S1070363207090186

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 9, pp. 1610 1613.
Original Russian Text I.V. Kulakov, O.A. Nurkenov, A.A. Ainabaev, D.M. Turdybekov, K.M. Turdybekov, A.M. Gazaliev, 2007, published in Zhurnal
Obshchei Khimii, 2007, Vol. 77, No. 9, pp. 1538 1541.
Pleiades Publishing, Ltd., 2007.
Steric Structure
of N-(2-Hydrazono-2-hydroxyethyl)-d-Pseudoephedrine and Its
Intramolecular Heterocyclization Under the Action
of Orthoformic Ester
I. V. Kulakova, O. A. Nurkenova, A. A. Ainabaeva, D. M. Turdybekovb,
K. M. Turdybekovb, and A. M. Gazalieva
a Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan,
ul. Alikhanova 1, Karaganda, 470061 Kazakhstan
e-mail: ivanku1@mail.ru
b Institute of Phytochemistry of the Republic of Kazakhstan, Karaganda, Kazakhstan
Received April 26, 2007
Abstract An X-ray structural investigation of N-(2-hydrazono-2-hydroxyethyl)-d-pseudoephedrine is
performed, and intramolecular heterocyclization of this compound with orthoformic ester is studied. The final
reaction product is found to be a compound containing a morpholone ring rather than substituted 1,3,4-oxadi-
azole.
DOI: 10.1134/S1070363207090186
The interest in the chemistry of hydrazides owes
to the fact that most hydrazide derivatives show a
broad-spectrum physiological activity, including a
pronounced antitubercular activity [1 5]. Earlier we
synthesized hydrazides and acylhydrazides of N-sub-
stituted aminoacetic acids derived from physiological-
ly active ephedrine alkaloids [6].
general view of the molecule is shown in the figure.
The crystal lattice of the molecule is found consisting
of a dimer.
The crystals of hydrazide I consist of two crystal-
lographically independent molecules whose bond
lengths (Table 1) and bond angles (Table 2) are close
to each other and to standard values [7]. An exception
are torsion angles (Table 3) which characterize the
molecular conformation of 1-ephedrine and its deriva-
To assess the steric structure of hydrazide I, we
performed an X-ray diffraction investigation. The
O4
C3
C2
C4
C24
C23
C1
C5
N6
C22
C21
C6
O1
C7
C8
N5
C20
N4
C19
C13
C10
C14
N2
N1
O3
C9
N3
C15
C18
C11
C17
C12
O2
C16
Molecular structure of N-(2-hydrazono-2-hydroxyethyl)-d-pseudoephedrine (I).
1610

STERIC STRUCTURE OF N-(2-HYDRAZONO-2-HYDROXYETHYL)-
Table 1. Bond angles ( , deg) in structure I Table 2. Bond lengths (d, ) in structure I
1611
Angle
Angle
Bond
d
Bond
d
C24N5N6
C23N4C22
C23N4C20
C22N4C20
C12N2N3
C11N1C10
C11N1C8
C10N1C8
O2C12N2
O2C12C11
N2C12C11
N4C20C21
N4C20C19
C21C20C19
O4C24N5
O4C24C23
N5C24C23
N4C23C24
N1C8C9
122.7(3)
110.8(3)
114.3(3)
111.4(3)
122.5(3)
110.9(3)
112.5(2)
113.4(3)
123.4(3)
120.9(3)
115.7(3)
115.2(3)
108.6(3)
112.3(3)
123.0(3)
121.3(3)
115.7(3)
113.4(3)
115.5(3)
106.9(3)
112.6(3)
114.2(3)
C6C1C2
118.6(4)
121.5(3)
119.9(3)
121.4(4)
117.5(4)
120.6(4)
121.7(3)
119.9(4)
121.9(4)
107.9(3)
109.0(3)
113.8(3)
120.7(4)
107.9(3)
109.4(3)
113.6(3)
120.1(4)
119.5(4)
118.9(4)
120.3(4)
120.3(4)
120.7(4)
N5C24
N5N6
1.332(4)
1.408(4)
1.232(4)
1.413(4)
1.455(4)
1.462(4)
1.486(4)
1.327(4)
1.229(4)
1.456(4)
1.461(4)
1.490(4)
1.518(4)
1.526(5)
1.532(5)
1.522(5)
1.422(5)
O3C19
1.404(5)
1.525(5)
1.537(4)
1.384(6)
1.384(5)
1.510(5)
1.373(6)
1.376(6)
1.365(5)
1.516(5)
1.360(7)
1.388(6)
1.385(6)
1.394(6)
1.366(8)
1.374(8)
1.384(7)
C6C1C7
C8C9
C2C1C7
O4C24
N3N2
C8C7
C17C18C13
C14C13C18
C14C13C19
C18C13C19
C16C15C14
C13C14C15
O1C7C1
C1C6
N4C23
N4C22
N4C20
N2C12
O2C12
N1C11
N1C10
N1C8
C1C2
C1C7
C18C17
C18C13
C13C14
C13C19
C15C16
C15C14
C2C3
O1C7C8
C1C7C8
C1C2C3
C12C11
C20C21
C20C19
C24C23
O1C7
O3C19C13
O3C19C20
C13C19C20
C1C6C5
C6C5
C4C5
C4C3
C16C17
C5C4C3
C15C16C17
C4C3C2
N1C8C7
C9C8C7
C18C17C16
C4C5C6
Table 3. Torsion angles ( , deg) in structure I
N1C11C12
Angle
Angle
tives. In the first molecule of the crystal they are as
follows: (C6C1C7O1) 54.2 , (O1C7C8N1) 54.3 ,
and (C7C8N1C10) 79.6 . The torsion angles in the
second molecule are as follows: (C18C13C19O3) 70.4 ,
(O3C19C20N4) 49.8 , and (C19C20N4C22) 149.2 .
N3N2C12O2
N3N2C12C11
C23N4C20C21
C22N4C20C21
C23N4C20C19
C22N4C20C19
N6N5C24O4
N6N5C24C23
C22N4C23C24
C20N4C23C24
O4C24C23N4
N5C24C23N4
C11N1C8C9
6.4(5) C2C1C7O1
176.2(3) C6C1C7C8
42.6(4) C2C1C7C8
83.8(4) N1C8C7O1
84.4(3) C9C8C7O1
149.1(3) N1C8C7C1
3.8(5) C9C8C7C1
123.1(4)
66.9(4)
115.9(4)
54.3(3)
177.9(3)
174.7(3)
57.5(4)
1.6(6)
175.7(4)
104.6(5)
70.5(5)
133.9(4)
51.0(5)
49.8(4)
178.5(4)
170.5(3)
60.8(4)
0.8(6)
The difference in the
angles is explained by the
formation of the following intramolecular hydrogen
bonds: N2 H H N6 (x, y, z) [r(N2 N6) 2.99 ),
177.2(3) C6C1C2C3
72.1(4) C7C1C2C3
161.2(3) C14C13C19O3
153.5(3) C18C13C19O3
27.4(4) C14C13C19C20
80.4(4) C18C13C19C20
46.5(4) N4C20C19O3
153.5(3) C21C20C19O3
79.6(3) N4C20C19C13
72.0(4) C21C20C19C13
159.7(3) C2C1C6C5
158.5(3) C7C1C6C5
23.9(4) C14C15C16C17
1.9(7) C5C4C3C2
N3 H H (x, y, z) [r(N3 N5) 2.97 )], N3 H O3
(x, y, z) [r(N3 O3) 2.99 , r(HN3A O3) 2.8 ), and
N6 H O1 (x, y, z) [r(N6 O1) 3.04 , r(HN6A O1)
2.8 ). Hydrogen bonding stabilizes the molecular
conformation and forms infinite tapes along the 21
[0, 0, y] axis.
C10N1C8C9
C11N1C8C7
Modification of hydrazides under the action of
appropriate reagents is known to be a useful method
for attenuating their toxicity and synthesizing new
dinitrogenous heterocycles. To correlate the biologic
activity of hydrazide I with its structure and synthesize
1,3,4-oxadiazoles on the basis of this compound, we
performed its condensation with orthoformic ester.
C10N1C8C7
C10N1C11C12
C8N1C11C12
O2C12C11N1
N2C12C11N1
C17C18C13C14
C17C18C13C19
C18C13C14C15
C19C13C14C15
C16C15C14C13
C6C1C7O1
176.4(4)
1.9(7)
1.5(7)
0.5(7)
1.0(8)
0.9(8)
2.2(7)
1.1(7)
177.1(4) C1C2C3C4
0.9(6) C13C18C17C16
176.2(4) C15C16C17C18
0.9(7) C3C4C5C6
Orthoformic ester is often used in heterocyclic
synthesis [8]. The use of orthoformic ester in the
synthesis of 1,3,4-oxadiazoles from carboxylic acid
hydrazides has been described [9]. The condensation
reaction was carried out by refluxing hydrazide I with
54.1(4) C1C6C5C4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 9 2007

1612
KULAKOV et al.
a 3-fold molar excess of orthoformic acid for 8 10 h.
Were the hydroxy group in the hydrazide molecule
inert, the reaction would afford a substituted 1,3,4-
oxadiazole by the following scheme:
OH
OH
CH(OC2H5)3
C6H5CH CHCH3
N CH3
C6H5CH CHCH3
H3C
N
O
CH2C(O)NHNH2
H2C
H
N
N
However, we isolated from the reaction mixture
(5S,6S)-4,5-dimethyl-6-phenylmorpholin-2-one (II)
which we used as the parent compound in the syn-
thesis of hydrazide I.
configuration of the resulting morpholone is the same
as that of the parent alkaloid.
Morpholone II is formed through intermediate
formation of hydrazones and transesterified substituted
esters, followed by intramolecular nucleophilic attack
of the alkoxyl oxygen on the electron-deficient car-
bonyl carbon, resulting in ring closure.
The formation of morpholone II was proved by
comparing its physicochemical constants, chemical
1
transformations, and H NMR spectrum with those of
the same compound synthesized earlier. The steric
OH
OCH(OC2H5)2
O
C6H5
CH3
O
CH(OC2H5)3
C6H5CH CHCH3
N CH3
C6H5CH CHCH3
N
CH3
N
O
CH2C(O)NHNH2
CH2
CH3
C
NHN=CHOC2H5
I
II
1
The H NMR spectrum of compound II contains a
doublet signal of CH CH3 methyl protons at 0.23 ppm
(J 5.0 Hz). The singlet at 1.65 ppm belongs to the
N-methyl group. The CH CH3 methine proton
appears as a multiplet in the region of 2.32 2.50 ppm,
and the CH O proton, as a doublet at 5.17 ppm.
Aromatic protons resonate in the region of 7.03 ppm.
Note that the NCH2C(O) methylene protons are non-
P4 automatic four-circle difractometer (MoK radia-
tion, graphite monochromator, /2 scanning, 2
52 ). The crystals are monoclinic, a 5.6892(5), b
<
35.363(2),
1269.37(17)
c
6.8257(5)
,
112.426(5) ,
V
4
3
3
,
dcalc 1.289 g cm ,
Z
(C24H38N6O4). Space group P21.
The calculations involved 2535 reflections with I >
2 (I). The structure was decoded by the direct method
using the SHELXS-97 program and refined by full-
matrix least squares anisotropically for nonhydrogen
atoms. Hydrogen atoms were located geometrically
and fixed by the rider model. Final divergence factors:
R 0.0477 and WR2 0.1356. Geometry refinement was
performed using the SHELXL-97 program. The co-
ordinates of nonhydrogen atoms are listed in Table 4.
a
c
equivalent (
2.72 and
3.37 ppm) and appear as
two doubletsHwith a coupliHng constant of 14.2 Hz.
EXPERIMENTAL
1
The H NMR spectra are recorded on a Tesla BS-
597 instrument at 80 MHz, solvent C6D6, internal re-
ference HMDS. The melting point was measured on a
Boetius hot stage.
(5S,6S)-4,5-Dimethyl-6-phenylmorpholin-2-one
(II). Orthoformic ester, 2.22 g (0.015 mol), was added
to 1.18 g (0.005 mol) of hydrazide I. The mixture was
X-Ray diffraction experiment. The unit cell
parameters and intensities of 2783 unique reflections
of compound I were measured at 20oC on a Brucker-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 9 2007

STERIC STRUCTURE OF N-(2-HYDRAZONO-2-HYDROXYETHYL)-
1613
Table 4. Atomic coordinates ( 104, for H 103) in struc-
ture I in cell fractions
refluxed for 8 h, after which it was diluted with chlo-
roform, filtered to remove a little precipitate, and
evaporated in a vacuum. The residue was subjected to
column chromatography on SiO2, eluent benzene, and
recrystallized from petroleum ether to isolate com-
pound II, mp 55 56 C.
Atom
x
y
z
N5
5495(5)
3668(5)
7648(6)
3265(5)
8332(5)
10307(5)
10432(5)
6170(6)
9703(6)
3434(6)
4231(5)
6686(6)
7443(7)
3547(6)
10221(6)
10413(6)
8436(6)
5471(9)
6656(7)
8898(10)
8374(8)
932(8)
12605(7)
9010(7)
9679(8)
6244(7)
12684(8)
6605(8)
7206(10)
2020(9)
7657(9)
9058(11)
5938(10)
6019(9)
2436(1)
2566(1)
2394(1)
3058(1)
2018(1)
1905(1)
1387(1)
2062(1)
1805(1)
3443(1)
2661(1)
1206(1)
3241(1)
3050(1)
989(1)
5532(4)
2042(4)
10246(4)
6508(4)
10015(4)
13511(4)
8995(4)
5270(4)
11656(5)
7433(5)
3902(5)
5169(5)
10011(6)
4477(5)
8236(5)
11117(5)
4776(5)
11358(7)
9961(6)
11191(8)
9913(7)
6367(8)
8858(6)
5803(5)
3495(6)
8644(6)
9060(7)
5011(7)
2639(7)
5868(7)
12519(7)
2428(8)
12612(7)
3948(8)
O4
N3
N4
REFERENCES
N2
O2
1. Medne, K.K., Materialy soveshchaniya po probleme
izyskaniya i izucheniya novykh lekarstvennykh prepa-
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N1
N6
C12
C20
C24
O1
2. Berdinskii, I.S., Sennitskaya, L.V., and Chereshne-
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O3
C23
C8
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C11
C1
1416(1)
616(1)
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C18
C13
C15
C14
C22
C10
C7
3954(1)
3897(1)
4482(1)
4163(1)
2866(1)
1589(1)
1002(1)
496(1)
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C19
C9
3540(1)
761(1)
383(1)
C6
C4
72(1)
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C21
C16
C3
3752(1)
4540(1)
154(1)
4271(1)
38(1)
C17
C5
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 9 2007