4-Hydroxy-2-quinolones 127. Simple method for exchanging chlorine for hydroxyl in 1-R-4-chloro-3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolines

Article abstract of DOI:10.1007/s10593-007-0177-8

Treatment of ethyl 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylates with sodium nitrite in DMSO is a convenient method for their conversion to the corresponding 4-hydroxy derivatives.

Full text of DOI:10.1007/s10593-007-0177-8

Chemistry of Heterocyclic Compounds, Vol. 43, No. 9, 2007
4-HYDROXY-2-QUINOLONES
127.* SIMPLE METHOD FOR EXCHANGING
CHLORINE FOR HYDROXYL IN 1-R-4-CHLORO-
-ETHOXYCARBONYl-2-OXO-1,2-DIHYDRO-
QUINOLINES
3
1
1
2
I. V. Ukrainets , N. L. Bereznyakova , and S. V. Shishkina
Treatment of ethyl 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylates with sodium nitrite in
DMSO is a convenient method for their conversion to the corresponding 4-hydroxy derivatives.
Keywords: 4-chloro-2-oxo-1,2-dihydroquinolines, nitrous acid esters, X-ray analysis.
At this time several methods are known for the preparation of ethyl 1-alkyl-4-hydroxy-2-oxo-
,2-dihydroquinoline-3-carboxylates which are widely used in the synthesis of biologically active molecules
1
[2-5]. With some considerable variety in the organic amines and 1,3-dicarbonyl compounds used in these
methods, they all show the common feature of the N-alkyl substituent being introduced into the amine
component before formation of the 4-hydroxy-2-oxo-1,2-dihydroquinoline ring. As is known, the N-alkylation
of anilines occurs far from smoothly. Hence we previously attempted to synthesise 1-alkyl-substituted
3
-ethoxycarbonyl-4-hydroxy-2-oxo-1,2-dihydroquinolines by a fundamentally different scheme proposing the
introduction of the alkyl substituent into the previously prepared 1H-quinolone [6]. Direct alkylation did not give
a positive result since it primarily gave the 4-alkoxyl derivative. With the use of a double excess of the
alkylating agent the N-alkylation can indeed be achieved but removal of the 4-O-alkyl-protecting group without
removal of the ethoxycarbonyl group remained a problem. On the other hand, the 4-O-acetyl protection is
removed quite readily as a result of which about 20% of the alkyl halides are consumed in the formation of side
alkyl acetates.
With this in mind, it seemed extremely promising to carry out a ready temporary modification of the
4
-hydroxy group to a chlorine which would be inert to the conditions of the subsequent alkylation [7]. In fact,
the N-alkylation of ethyl 4-chloro-1H-2-oxo-1,2-dihydroquinoline-3-carboxylates occurs in good yields [6].
However, as in the case with the 4-alkoxy derivatives, the return conversion of chlorine to a hydroxyl group is
also significantly complicated by the lability of the ester reaction center in the molecule. None the less, we have
unexpectedly discovered a very simple solution to this problem.
_
*
______
For Communication 126 see [1].
_
_________________________________________________________________________________________
1
2
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. STC "Institute
for Single Crystals", Ukraine National Academy of Sciences, Kharkiv 61001; e-mail:
svet@xray.isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1359-1364,
September, 2007. Original article submitted May 18, 2006.
1
154
0009-3122/07/4309-1154©2007 Springer Science+Business Media, Inc.

Being an ambident nucleophile the nitrite ion can react with organic halides in two ways. Depending on
the conditions, the attack can occur at either the oxygen or a nitrogen atom leading to a nitrous acid ester or nitro
derivative respectively [8]. Put differently, the reaction of ethyl 4-chloro-1-ethyl-2-oxo-1,2-dihydroquinoline-3-
carboxylate (1) with sodium nitrite can theoretically form both the 4-nitroquinolone 2 and the hetarylnitrite 3.
Aprotic solvents cannot form hydrogen bonds and are thus unable to strongly solvate the anions formed on
dissociation. As a result, when the reaction is carried out in DMSO the nitrite ion oxygen (as the center with the
greatest charge density) proves more basic than the nitrogen and hence the O-substitution principally occurs.
Cl
NO2
CO Et
CO Et
2
2
NaNO , DMSO
2
N
Et
1
O
N
O
Et
2
NaNO , DMSO,
DMSO, 60°С, 48 h
2
2
0°С, 10 h
N
O
O
N
OH
CO Et
CO Et
2
H O
2
2
O
N
Et
4
O
Et
3
The compound obtained gives a negative Beilstein test hence nucleophilic substitution of halogen in the
chloroquinoline 1 has occurred successfully. However, X-ray analysis carried out by us (Figure 1, Tables 1, 2)
Fig. 1. Structure of the 4-hydroxy ester 4 molecule with atomic numbering.
1
155

TABLE 1. Bond Lengths (l) in the 4-Hydroxy Ester 4 Structure
Bond
l, Å
Bond
l, Å
Bond
l, Å
N
N
O
O
(1A)–C(1A)
(1A)–C(13A)
(2A)–C(7A)
(4A)–C(10A)
1.394(3)
1.466(3)
1.330(3)
1.315(3)
1.393(3)
1.370(3)
1.373(3)
1.434(3)
1.456(3)
1.496(3)
1.391(3)
1.466(3)
1.333(3)
1.321(3)
C
C
C
C
C
C
(1B)–C(6B)
(2B)–C(3B)
(4B)–C(5B)
(6B)–C(7B)
(8B)–C(9B)
(11B)–C(12B)
1.402(3)
1.381(3)
1.371(3)
1.429(3)
1.467(3)
1.499(3)
1.407(3)
1.227(2)
1.236(3)
1.459(3)
1.408(3)
1.378(4)
1.402(3)
1.383(3)
C
C
N
O
O
O
(8A)–C(10A)
(13A)–C(14A)
1.468(3)
1.515(3)
1.405(3)
1.221(3)
1.234(3)
1.457(3)
1.408(3)
1.379(4)
1.408(3)
1.378(3)
1.470(3)
1.514(3)
(1B)–C(9B)
(1B)–C(9B)
(3B)–C(10B)
(4B)–C(11B)
C
C
C
C
C
C
(1A)–C(6A)
(2A)–C(3A)
(4A)–C(5A)
(6A)–C(7A)
(8A)–C(9A)
(11A)–C(12A)
N
O
O
O
(1A)–C(9A)
(1A)–C(9A)
(3A)–C(10A)
(4A)–C(11A)
C
C
C
C
C
C
(1B)–C(2B)
(3B)–C(4B)
(5B)–C(6B)
(7B)–C(8B)
(8B)–C(10B)
(13B)–C(14B)
N(1B)–C(1B)
N(1B)–C(13B)
O(2B)–C(7B)
O(4B)–C(10B)
C
C
C
C
(1A)–C(2A)
(3A)–C(4A)
(5A)–C(6A)
(7A)–C(8A)
has shown that this compound is neither the nitroquinolone 2 nor the hetarylnitrite 3 but it is ethyl 1-ethyl-4-
hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (4). In the symmetrically independent part of the unit cell
this compound exists as two molecules (A and B), differing in some geometrical parameters.
TABLE 2. Valence Angles (ω) in the 4-Hydroxy Ester 4 Structure
Angle
ω, deg
Angle
ω, deg
C
C
C
(1A)–N(1A)–C(9A)
(9A)–N(1A)–C(13A)
(6A)–C(1A)–N(1A)
123.3(2)
116.2(2)
119.8(2)
121.3(2)
121.8(2)
120.4(2)
118.8(2)
122.7(2)
121.4(2)
118.0(2)
118.4(2)
116.5(2)
121.5(2)
110.9(2)
123.9(2)
115.3(2)
119.4(2)
118.7(2)
121.5(2)
120.8(2)
118.8(2)
122.3(2)
121.8(2)
118.1(2)
119.1(2)
116.0(2)
121.8(2)
111.1(2)
C
C
C
C
C
C
C
(1A)–N(1A)–C(13A)
(10A)–O(4A)–C(11A)
(6A)–C(1A)–C(2A)
(3A)–C(2A)–C(1A)
(5A)–C(4A)–C(3A)
(1A)–C(6A)–C(5A)
(5A)–C(6A)–C(7A)
120.5(2)
117.5(2)
118.8(2)
119.6(2)
119.3(2)
120.0(2)
121.2(2)
115.9(2)
120.0(2)
122.0(2)
125.1(2)
122.0(2)
116.5(2)
112.0(2)
120.7(2)
117.9(2)
121.9(2)
119.9(2)
119.5(2)
119.7(2)
121.5(2)
115.9(2)
120.0(2)
122.0(2)
124.9(2)
121.6(2)
116.6(2)
111.8(2)
N
(1A)–C(1A)–C(2A)
C
C
C
(2A)–C(3A)–C(4A)
(4A)–C(5A)–C(6A)
(1A)–C(6A)–C(7A)
O
(2A)–C(7A)–C(8A)
O(2A)–C(7A)–C(6A)
C
C
(8A)–C(7A)–C(6A)
(7A)–C(8A)–C(10A)
C
C
(7A)–C(8A)–C(9A)
(9A)–C(8A)–C(10A)
O
N
O
O
(1A)–C(9A)–N(1A)
(1A)–C(9A)–C(8A)
(3A)–C(10A)–C(8A)
(4A)–C(11A)–C(12A)
O
O
O
N
(1A)–C(9A)–C(8A)
(3A)–C(10A)–O(4A)
(4A)–C(10A)–C(8A)
(1A)–C(13A)–C(14A)
C
C
(1B)–N(1B)–C(9B)
(9B)–N(1B)–C(13B)
C
C
(1B)–N(1B)–C(13B)
(10B)–O(4B)–C(11B)
N
(1B)–C(1B)–C(6B)
N(1B)–C(1B)–C(2B)
C
C
C
C
(6B)–C(1B)–C(2B)
(4B)–C(3B)–C(2B)
(4B)–C(5B)–C(6B)
(1B)–C(6B)–C(7B)
C
C
C
C
(3B)–C(2B)–C(1B)
(5B)–C(4B)–C(3B)
(1B)–C(6B)–C(5B)
(5B)–C(6B)–C(7B)
O
(2B)–C(7B)–C(8B)
O(2B)–C(7B)–C(6B)
C
C
(8B)–C(7B)–C(6B)
(7B)–C(8B)–C(10B)
C
C
(7B)–C(8B)–C(9B)
(9B)–C(8B)–C(10B)
O
N
O
O
(1B)–C(9B)–N(1B)
(1B)–C(9B)–C(8B)
(3B)–C(10B)–C(8B)
(4B)–C(11B)–C(12B)
O
O
O
N
(1B)–C(9B)–C(8B)
(3B)–C(10B)–O(4B)
(4B)–C(10B)–C(8B)
(1B)–C(13B)–C(14B)
1
156

In both molecules all of the non-hydrogen atoms lie within a single plane to an accuracy of 0.03 Å with
the exception of C(12) and C(14) and an intramolecular hydrogen bond can be formed in both the A and B
molecules via O –H(2O)···O(3) (H···O 1.76 Å, O–H···O 148º). A shortened intramolecular contact H ···O of
(
2)
(5)
(2)
2
.43 in A and 2.44 Å in B additionally occurs (sum of the van der Waal radii 2.46 Å [9]). Overall, the bond
lengths in the structure of ester 4 are similar to chose in the previously studied 4-hydroxy-2-oxoquinolines
[
10, 11].
The ethyl group of the ester substituent is placed perpendicularly to the plane of the bicyclic fragment
torsional angle C(10)–O –C(11)–C(12) 88.1(3) in A and 87.1(3) in B) with causes a shortened intramolecular
(
(4)
contact H(11b)···O of 2.36 in A and 2.37 Å in B (2.46 Å).
(3)
The substituent on atom N(1) is also placed perpendicularly to the bicyclic plane (torsional angle
C –N –C(13)–C(14) -91.7(2) in A and -90.7(2)º in B) with repulsion between it and the neighboring carbonyl
(
9)
(1)
group and hydrogen atom in the peri position of the benzene ring [shortened intramolecular contacts H ···C
(13)
(
2)
2
.54 in A, 2.56 in B (2.87); H ···H
(13b)
2.02 A, 2.04 B (2.34), H(13a)···O(1) 2.30 A, 2.28 B (2.46), H(13b)···C(2) 2.55
(
2)
A 2.56 B (2.87 Å)] leading to increased bond lengths N –C 1.394(3) A, 1.391(3) B and N –C 1.407(3) A,
(
1)
(1)
(1)
(9)
1
.405(3) Å B when compared with their mean values [12] (1.353 and 1.355 Å respectively). A shortened
intermolecular contact H(3a)···H(14b)’ is also found between the molecules in the crystal of 4 (1-x, 1-y, 1-z) 2.31 Å
2.34 Å).
Formation of the 4-hydroxy ester 4 from the 4-nitroquinolone 2 is impossible hence it can be
(
unambiguously proved that the first stage of the reaction of the chloro derivative 1 with sodium nitrite in DMSO
is undoubtedly O-substitution to give the hetarylnitrite 3. Being virtually an enol nitrous acid ester this
compound is very readily hydrolyzed to give the 4-hydroxy ester 4 in high yield in the final step.
Attention should also be paid the fact that some halo derivatives, e.g. ethyl 4-chloroquinoline-
3
-carboxylate is converted to the hydroxyl compound under the action of just DMSO [13]. However, a similar
reaction cannot be achieved with the 4-chloro-substituted ester 1 so we can exclude this conversion to the
hydroxyl compound 4 from a number of options.
Hence, through the results of carrying out the workup with sodium nitrite in DMSO solution we can
recommend this method as a preparative procedure for exchanging chlorine for a hydroxyl group in 1-R-2-oxo-
4
-chloro-3-ethoxycarbonyl-1,2-dihydroquinolines.
EXPERIMENTAL
Ethyl 1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (4). NaNO (0.76 g, 0.011 mol)
2
was added to a solution of the ethyl 4-chloro-1-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (1) [6] (2.79 g,
0
.01 mol) in DMSO (15 ml), stirred until dissolved, and left for 10 h at room temperature. The reaction mixture
was diluted with water. The precipitated 4-hydroxy ester 4 was filtered off, washed with water, and dried. Yield
.38 g (91%). A single crystal suitable for X-ray analysis with mp 66-68ºC was obtained by crystallization from
2
ether. When mixed with a known sample [4] the melting point was not depressed.
X-ray Analysis. Crystals of ester 4 are triclinic, at 20ºC: a = 7.348(2), b = 11.240(6), c = 16.426(4) Å,
3
3
α = 87.72(3), β = 77.63(2), γ = 72.92(3)º, V = 1266.2(8), Å , M = 261.27, Z = 4, space group P1, d = 1.371 g/cm ,
r
calc
-1
µ(MoKα) = 0.101 mm , F(000) = 552. The unit cell parameters and intensities of 11,456 reflections (5812
independent with Rint = 0.035) were measured on an Xcalibur-3, four circle automatic diffractometer (MoKα
radiation, CCD detector, graphite monochromator, ω scanning, 2θmax = 55º).
The structure was solved by a direct method using the SHELXTL [14] program package. The positions
of the hydrogen atoms were revealed from the electron density difference synthesis and refined using the
"
riding" model with Uiso =nU for a non-hydrogen atom bound with the given hydrogen (n = 1.5 for a methyl
eq
2
group and n = 1.2 for remaining hydrogen atoms). The structure was refined by F full matrix least squares
1
157

analysis in the anisotropic approximation for non hydrogen atoms to wR
2
= 0.148 for 5773 reflections
(R1 = 0.056 for 2756 reflections with F > 4σ(F), S = 0.973). The complete crystallographic data have been
placed in the Cambridge structural data base, reference CCDC 608699. The interatomic distances and valence
angles are given in Tables 1 and 2.
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