Synthesis and structure of 3-(3-acetoxyalkylcarbamoyl-4-hydroxy-2-oxo-1,2- dihydroquinolin-1-yl)propanoic acids

Article abstract of DOI:10.1134/S1070428014010126

Treatment of 1-(2-cyanoethyl)-4-hydroxy-N-(hydroxyalkyl)-2-oxo-1,2- dihydroquinoline-3-carboxamides with a solution of hydrogen chloride in aqueous acetic acid ensures selective transformation of the cyano group into amide or carboxy with simultaneous acetylation of the hydroxyalkyl fragments.

Full text of DOI:10.1134/S1070428014010126

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 63–65. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © I.V. Ukrainets, O.V. Gorokhova, K.V. Andreeva, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 1, pp. 69–71.
Synthesis and Structure of 3-(3-Acetoxyalkylcarbamoyl-
4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic Acids
I. V. Ukrainets, O. V. Gorokhova, and K. V. Andreeva
National University of Pharmacy, ul. Pushkinskaya 53, Kharkiv, 61002 Ukraine
e-mail: uiv-2@mail.ru
Received July 17, 2013
Abstract—Treatment of 1-(2-cyanoethyl)-4-hydroxy-N-(hydroxyalkyl)-2-oxo-1,2-dihydroquinoline-3-carbox-
amides with a solution of hydrogen chloride in aqueous acetic acid ensures selective transformation of the
cyano group into amide or carboxy with simultaneous acetylation of the hydroxyalkyl fragments.
DOI: 10.1134/S1070428014010126
We previously proposed a procedure for selective
hydration of 3-(3-R-carbamoyl-4-hydroxy-2-oxo-1,2-
dihydroquinolin-1-yl)propanenitriles into the corre-
sponding propanamides by treatment with a solution of
HCl in acetic acid with a low concentration of water,
which may be useful in the search for new non-
narcotic analgesics [1]. If necessary, prolonged reac-
tion time makes it possible to accomplish profound
transformations, in particular hydrolysis of the initially
formed propanamides to 3-(quinolin-1-yl)propanoic
acids which may be interesting as models for structural
biological studies [1, 2] and substrates for various sub-
sequent modifications.
the substituent in the benzyl fragment and ranged from
negligible to almost complete [1].
1-(2-Cyanoethyl)-4-hydroxy-N-(hydroxyalkyl)-2-
oxo-1,2-dihydroquinoline-3-carboxamides Ia and Ib
also showed some specificity in the reaction with HCl–
1
AcOH–H2O. The H NMR spectra of the isolated
products clearly showed stepwise transformation of the
cyano group in these compounds first into amide and
then into carboxy. On the other hand, in all cases the
1H NMR spectra lacked signal assignable to alcoholic
hydroxy proton; instead, an additional three-proton
singlet appeared in a strong field. These findings led us
to presume that the hydration (hydrolysis) of cyano
group in hydroxyalkylamides Ia and Ib in the system
HCl–AcOH–H2O is accompanied by O-acetylation to
produce acetoxyalkylcarbamoyl derivatives IIa and
IIb (propanamides) or IIIa and IIIb (propanoic acids;
Scheme 1).
In fact, our assumption was unambiguously con-
firmed by X-ray analysis of acid IIIb (see figure). It is
interesting that the described reactions combine, as it
may seem, two mutually exclusive processes under the
same conditions, hydrolysis of the amide (cyano) group
3-(3-R-Carbamoyl-4-hydroxy-2-oxo-1,2-dihydro-
quinolin-1-yl)propanenitriles behaved similarly in the
examined reaction, and all steps of their successive
transformations into propanamides and then propanoic
acids gave reproducibly good results. However, some
deviations from the general pattern were possible if the
reaction involved other molecular fragments in ad-
dition to the cyano group. For example, 3-benzyl-
carbamoyl derivatives in the system HCl–AcOH–H2O
underwent N-debenzylation whose extent depended on
Scheme 1.
OH
O
OAc
( )n
OH
O
OH
( )n
OH
O
OAc
( )n
AcOH, HCl, H2O
80°C, 2 h
AcOH, HCl, H2O
80°C, 15 h
N
N
N
H
H
H
N
O
N
O
N
O
CONH2
IIa, IIb
CN
COOH
IIIa, IIIb
Ia, Ib
n = 2 (a), 3 (b).
63

UKRAINETS et al.
64
and esterification. Moreover, it is surprising that the
acetoxyalkyl fragment in II and III remains intact in
the system HCl–AcOH–H2O which was originally
proposed [3, 4] just for hydrolysis of esters.
[1.251(1) Å] and O3–C10 bonds [1.266(2) Å] relative to
the standard C=O bond (1.210 Å [5]), whereas the
O2–C7 [1.318(1) Å], N2–C10 [1.322(2) Å], and C8–C9
bonds [1.436(2) Å] are shortened (standard values
1.362, 1.334, and 1.455 Å, respectively). The C7–C8
bond is extended to 1.384(2) Å (against 1.326 Å),
which is typical of 4-hydroxyquinolin-2-ones.
The substituent on the amide nitrogen atom occu-
pies antiperiplanar position with respect to the C8–C10
bond [torsion angle C8C10N2C11 178.7(1)°] and adopts
–sc/–sc conformation [torsion angles C10N2C11C12
–82.1(2)° and N2C11C12C13 –64.2(2)°]. The acetoxy
group is antiperiplanar with respect to the C11–C12
bond and is almost coplanar to the C12–C13 bond
[torsion angles C11C12C13O4 177.6(1)° and C14O4C13C12
–171.5(1)°]. Attractive H5 ···O2 interaction (2.40 Å)
should also be noted (the sum of the van der Waals
radii 2.46 Å).
Let us note some structural features of molecule
IIIb (for atom numbering, see figure). The dihydro-
pyridine ring slightly deviates from planarity [endo-
cyclic torsion angles C9N1C1C6 5.7(2)°, C1N1C9C8
–6.7(2)°], which may be due to fairly strong steric
repulsion between the carboxyethyl group, neighboring
atoms of the aromatic ring, and carbonyl group in the
vicinal position [shortened intramolecular contacts
H2 ···C16 2.58 Å (the sum of the van der Waals radii
2.87 Å [5]), H2 ···H16a 2.11 (2.34), H16a ···C2 2.58
(2.87), H16b···O1 2.35 Å (2.46 Å)]. The same steric
repulsions are responsible for extension of the N1–C16
[1.478(2)], N1–C9 [1.376(2)], and N1–C1 bonds
[1.394(1) Å] relative to the corresponding standard
bonds (1.469, 1.353, and 1.371 Å, respectively [6]).
Molecules IIIb in crystal are linked through fairly
strong intermolecular H-bonds O7–H7O···O1' (0.5 – x,
–0.5 + y, 1.5 – z; H···O 1.66 Å, ∠OHO 177°) to form
infinite chains along the [010] crystallographic axis.
Correspondingly, the O7–C18 bond [1.316(2) Å] is
appreciably shorter than the reference value (1.362 Å).
The terminal carboxymethylene fragment in the
substituent on N1 is oriented orthogonally to the pyri-
dine ring plane [torsion angle C9N1C16C17 89.7(1)°],
and the carboxy group appears in the antiperiplanar
orientation with respect to the N1–C16 bond and is
slightly turned about the C16–C17 bond [torsion angles
N1C16C17C18 –179.6(1)° and C16C17C18O6 14.6(2)°].
The amide fragment in the substituent on C8 is almost
coplanar to the dihydropyridine ring plane due to
formation of strong intramolecular hydrogen bonds
N2–H2N · · · O1 (H · · · O 1.99 Å, ∠NHO 137°) and
O2–H2O ···O3 (H···O 1.54 Å, ∠OHO 155°). These
H-bonds also induce elongation of the O1–C9
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury-VX-200 spectrometer (200 MHz) from solu-
tions in DMSO-d6 using tetramethylsilane as internal
reference. The elemental compositions were deter-
mined on a EuroVector EA-3000 micro analyzer. The
melting points were measured in capillaries on a Stuart
SMP10 digital melting point apparatus and were not
corrected. The synthesis and properties of initial
1-(2-cyanoethyl)-4-hydroxy-N-(hydroxyalkyl)-2-oxo-
1,2-dihydroquinoline-3-carboxamides Ia and Ib were
reported in [7].
2-[4-Hydroxy-1-(2-carbamoylethyl)-2-oxo-1,2-di-
hydroquinolin-3-ylcarboxamido]ethyl acetate (IIa).
A mixture of 3.01 g (0.01 mol) of nitrile Ia and 20 mL
of a ~2.8 M solution of HCl in acetic acid with low
water content (prepared by mixing required amounts of
acetic anhydride and concentrated aqueous HCl ac-
cording to the procedure described in [3]) was heated
for 2 h at 80°C. The mixture was cooled and diluted
with 50 mL of cold water, and the precipitate was
filtered off, washed with water, and dried. Yield 2.82 g
(78%), colorless crystals, mp 179–181°C (from EtOH).
1H NMR spectrum, δ, ppm: 2.02 s (3H, CH3), 2.43 t
(2H, N1CH2CH2, J = 7. 4 Hz), 3. 62 q (2H,
NHCH2CH2O, J = 5.6 Hz), 4.17 t (2H, NHCH2CH2O,
O2
O3
C5
C4
C7
C10 C11
N2
C12
O4
C15
C6
C1
C8
C9
C13
C14
C3
C2
N1
C16
C18
O1
O5
C17
O6
O7
Structure of the molecule of 3-[3-(3-acetoxypropylcarba-
moyl)-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl]propanoic
acid (IIIb) according to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

SYNTHESIS AND STRUCTURE OF 3-(3-ACETOXYALKYLCARBAMOYL-...
65
J = 5.4 Hz), 4.42 t (2H, N1CH2CH2, J = 7.5 Hz), 6.95 s
(1H, CH2CONH2), 7.36 t (1H, 6-H, J = 7.5 Hz), 7.45 s
(1H, CH2CONH2), 7.67 d (1H, 8-H, J = 8.8 Hz), 7.80 t
(1H, 7-H, J = 7.7 Hz), 8.10 d (1H, 5-H, J = 7.9 Hz),
10.42 t (1H, 3-CONH, J = 5.9 Hz), 17.20 s (1H, OH).
Found, %: C 56.60; H 5.41; N 11.54. C17H19N3O6. Cal-
culated, %: C 56.51; H 5.30; N 11.63.
5-H, J = 8.1 Hz), 10.34 t (1H, CONH, J = 5.9 Hz),
12.43 br.s (1H, COOH), 17.42 s (1H, 4-OH). Found,
%: C 57.57; H 5.43; N 7.50. C18H20N2O7. Calculated,
%: C 57.44; H 5.36; N 7.44.
X-Ray diffraction data for compound IIIb.
Monoclinic crystals (from EtOH) with the following
unit cell parameters (20°C): a = 7.4313(3), b =
11.7269(5), c = 20.2090(7) Å; β = 94.660(3)°; V =
1755.3(1) Å3; M 376.36; Z = 4; space group P21/n;
dcalc = 1.424 g/cm3; μ(MoKα) = 0.111 mm–1; F(000) =
792. The unit cell parameters and intensities of
Compounds IIb, IIIa, and IIIb were synthesized in
a similar way, but in the synthesis of IIIa and IIIb the
reaction mixture was heated for 15 h.
3-[1-(2-Carbamoylethyl)-4-hydroxy-2-oxo-1,2-di-
hydroquinolin-3-ylcarboxamido]propyl acetate
(IIb). Yield 2.74 g (73%), colorless crystals, mp 182–
20111 reflections (5126 independent reflections, Rint
=
0.025) were measured on an Xcalibur-3 diffractometer
(MoKα radiation, CCD detector, graphite mono-
chromator, ω-scanning, 2θmax = 60°). The structure
was solved by the direct method using SHELXTL
software package [8]. The positions of hydrogen atoms
were determined by difference synthesis of electron
density and were refined in isotropic approximation.
The structure was refined against F2 by the full-matrix
least-squares method in anisotropic approximation for
non-hydrogen atoms; wR2 = 0.141 for 5057 reflections
[R1 = 0.047 for 3411 reflections with F > 4σ(F)]; good-
ness of fit S = 1.015. The complete set of crystallo-
graphic data for compound IIIb was deposited to
the Cambridge Crystallographic Data Centre (entry
no. CCDC 940243).
1
184°C (from EtOH). H NMR spectrum, δ, ppm:
1.88 q (2H, NHCH2CH2CH2O, J = 6.4 Hz), 2.02 s (3H,
CH3), 2.42 t (2H, N1CH2CH2, J = 7.2 Hz), 3.45 q
(2H, NHCH2CH2CH2O, J = 6.2 Hz), 4.07 t (2H,
NHCH2CH2CH2O, J = 6. 1 Hz), 4. 41 t (2H,
N1CH2CH2, J = 7.2 Hz), 6.94 s (1H, CH2CONH2),
7.35 t (1H, 6-H, J = 7.5 Hz), 7.44 s (1H, CH2CONH2),
7.65 d (1H, 8-H, J = 8.7 Hz), 7.79 t (1H, 7-H, J =
7.6 Hz), 8.08 d (1H, 5-H, J = 8.0 Hz), 10.37 t (1H,
3-CONH, J = 5.7 Hz), 17.38 s (1H, OH). Found, %:
C 57.72; H 5.55; N 11.07. C18H21N3O6. Calculated, %:
C 57.59; H 5.64; N 11.19.
3-[3-(2-Acetoxyethylcarbamoyl)-4-hydroxy-2-
oxo-1,2-dihydroquinolin-1-yl]propanoic acid (IIIa).
Yield 3.04 g (84%), colorless crystals, mp 171–173°C
REFERENCES
1
(from EtOH). H NMR spectrum, δ, ppm: 2.01 s (3H,
CH3), 2.56 t (2H, N1CH2CH2, J = 7.5 Hz), 3.61 q (2H,
NHCH2CH2O, J = 5.5 Hz), 4.18 t (2H, NHCH2CH2O,
J 5.5 Hz), 4.45 t (2H, N1CH2CH2, J = 7.5 Hz), 7.35 t
(1H, 6-H, J = 7.4 Hz), 7.65 d (1H, 8-H, J = 8.6 Hz),
7.79 t (1H, 7-H, J = 7.6 Hz), 8.08 d (1H, 5-H, J =
8.1 Hz), 10.37 t (1H, CONH, J = 6.1 Hz), 12.45 br.s
(1H, COOH), 17.22 s (1H, 4-OH). Found, %: C 56.28;
H 4.93; N 7.81. C17H18N2O7. Calculated, %: C 56.35;
H 5.01; N 7.73.
1. Ukrainets, I.V., Gorokhova, O.V., and Andreeva, K.V.,
Russ. J. Org. Chem., 2013, vol. 49, p. 867.
2. Ukrainets, I.V., Andreeva, K.V., Gorokhova, O.V., and
Kravchenko, V.N., Khim. Geterotsikl. Soedin., 2012,
p. 1932.
3. Jönsson, S., Andersson, G., Fex, T., Fristedt, T., Hed-
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ski, O., Runström, A., Sandin, H., Thuvesson, I., and
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Soedin., 2010, p. 706.
3-[3-(3-Acetoxypropylcarbamoyl)-4-hydroxy-2-
oxo-1,2-dihydroquinolin-1-yl]propanoic acid (IIIb).
Yield 3.01 g (80%), colorless crystals, mp 164–166°C
5. Zefirov, Yu.V., Kristallografiya, 1997, vol. 42, p. 936.
6. Structure Correlation, Bürgi, H.-B. and Dunitz, J.D.,
1
(from EtOH). H NMR spectrum, δ, ppm: 1.87 q (2H,
NHCH2CH2CH2O, J = 6.3 Hz), 2.01 s (3H, CH3),
2.57 t (2H, N1CH2CH2, J = 7.5 Hz), 3.45 q (2H,
NHCH2CH2CH2O, J = 6.1 Hz), 4.08 t (2H, NHCH2-
CH2CH2O, J = 6.1 Hz), 4.45 t (2H, N1CH2CH2, J =
7.5 Hz), 7.37 t (1H, 6-H, J = 7.4 Hz), 7.66 d (1H, 8-H,
J = 8.6 Hz), 7.80 t (1H, 7-H, J = 7.8 Hz), 8.10 d (1H,
Eds., Weinheim: VCH, 1994, vol. 2, p. 741.
7. Ukrainets, I.V., Gorokhova, O.V., Andreeva, X.V.,
and Sim, G., Int. J. Pharm. Pharmacol., 2012, vol. 1,
no. 3, p. 33.
8. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008, vol. 64,
p. 112.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014