4-Hydroxy-2-quinolones. 109. Alkylation of 4-substituted ethyl 2-oxo-1,2-dihydro-quinoline-3-carboxylates

Article abstract of DOI:10.1007/s10593-006-0238-4

The alkylation of the ethyl esters of 4-methyl, 4-chloro-, and 4-amino substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acid by ethyl iodide in the system DMF/K₂CO₃ has been studied. Features of the structure of the starting compounds and their effect on the ratio of the N-and O-alkyl products formed are discussed.

Full text of DOI:10.1007/s10593-006-0238-4

Chemistry of Heterocyclic Compounds, Vol. 42, No. 10, 2006
4-HYDROXY-2-QUINOLONES. 109*. ALKYLATION
OF 4-SUBSTITUTED ETHYL 2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBOXYLATES
I. V. Ukrainets1, L. V. Sidorenko1, O. V. Gorokhova1, N, L. Bereznyakova1, and S. V. Shishkina2
The alkylation of the ethyl esters of 4-methyl, 4-chloro-, and 4-amino substituted 2-oxo-1,2-
dihydroquinoline-3-carboxylic acid by ethyl iodide in the system DMF/K2CO3 has been studied.
Features of the structure of the starting compounds and their effect on the ratio of the N- and O-alkyl
products formed are discussed.
Keywords: 2-oxo-1,2-dihydroquinolines, 1H-quinolin-2-ones, alkylation, X-ray structural analysis.
The alkylation of α-oxo(hydroxyl)azaheterocycles rarely proceeds uniquely. As a rule the result of such
reactions are a mixture of the corresponding N- and O-alkyl substituted derivatives, frequently containing some
of the starting material [2-5]. The predominant formation of one of the isomers is determined by many factors
including the substituents in the alkylating substance, the structure and size of the introduced alkyl group (in the
case of alkyl halides the halogen has an important effect), the base used for generating the anion, the solvent, and
other experimental reaction conditions. Hence the effect of external and structural factors on the alkylation of α-
oxo(hydroxy)azaheterocycles is of special interest and has become the subject of many investigations [5-7].
The experiments carried out by us have shown that alkylation of ethyl 4-methyl-2-oxo-1,2-
dihydroquinoline-3-carboxylate (1a) by ethyl iodide in the system DMF/K2CO3 (i.e. essentially the ambident
anion 2a) gives a mixture of reaction products. According to mass spectroscopic data the main component (70%)
is the N-ethylquinolone 3a. A minor residue (28%) was identified as 2-ethoxyquinoline 4a with 2% of the non
reacting starting NH-ester 1a. As is known [6] ,the alkylation route for this type of compound depends to a large
extent on the position of the tautomeric equilibrium. Through a detailed study of the structure of ester 1a we
have previously noted some of its features. In particular, a marked delocalization of electron density into the
quinoline fragment is observed and this allowed us to suggest that the ester 1a exists in neutral conditions in two
tautomeric forms, i.e. aromatic and 1,2-dihydro with the latter predominating [8]. In basic medium the
contribution of the aromatic tautomer towards the resonance hybrid is essentially unchanged and as a result the
alkylation of ester 1a gives a high yield of the 1-N-substituted product 3a.
_______
* For Communication 108 see [1].
__________________________________________________________________________________________
1 National Pharmaceutical University, Kharkiv, 61002, Ukraine; e-mail: univ@kharkov.ua. 2 Institute for
Scintillation Materials, Ukraine National Academy of Sciences, Kharkiv, 61001; e-mail:
sveta@xray.isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1502-1507,
October, 2006. Original article submitted June 27, 2005.
1296
0009-3122/06/4210-1296©2006 Springer Science+Business Media, Inc.

R
N
O
O
OEt
–
+
K
2a–c
EtI, DMF
R
O
O
R
O
R
O
O
OEt
OEt
OEt
OEt
+
+
N
Et
N
N
H
3a–c
4a–c
1a–c
1-4: a
R = Me 70%
28%
31%
95%
2%
R = Cl
69%
1%
0
b
c
R = NH2
4%
By contrast, in the structural analog of the 4-methyl-substituted ester 1a (ethyl 4-chloro-2-oxo-1,2-
dihydroquinoline-3-carboxylate 1b) the double bond C(7)–C(8) is localized according to X-ray analysis (Figure 1,
Tables 1 and 2). Some lengthening of the C(9)–O(1) carbonyl bond (1.242(4) Å, mean value 1.210 Å [9]) can be
explained not by tautomerism but just by the formation of an intermolecular hydrogen bond N(1)–H(1)···O(1) (-1-x,
2-y, 1-z) H···O 1.98 Å, N–H···O 171°. The bicyclic fragment and atoms O(1) and Cl(1) lie in a single plane to
within 0.01 Å. The ester group at atom C(8) is randomized into two positions A and B with a conformational
population density of 54:46 as a result of rotation around the C(8)–C(10) bond and in both conformers turned
practically perpendicularly to the quinoline plane as in the 4-methyl-substituted ester 1a (torsional angle C(7)–
C(8)–C(10)–O(2) -88(1)° in A and -108(1)° in B). The ethyl group in conformers A and B is found in an ap-
position relative to the C(10)–C(8) bond (torsional angles C(11)–O(3)–C(10)–C(8) -166.3(9)° in A and -171(1)° in B).
In the conformer A the C(12) atom is found in a position intermediate between -ac and -ap but in conformer B
close to +ac (torsional angles C(10)–O(3)–C(11)–C(12) -166(1)° in A and 147(2)° in B). Moreover, in conformer A a
shortening of the intramolecular contact H(11b)–O(2a) occurs (2.35 Å, sum of van der Waal radii 2.46 Å, [10]). The
molecule also shows a shortened H(5)···Cl(1) contact of 2.71 Å (3.06 Å). In other words, the X-ray analysis of the
chloro-substituted ester 1b does not permit conformation of any marked presence of an aromatic tautomeric form
in the crystal. Hence in the alkylation of this quinolone by ethyl iodide it would be logical to expect, if not
exclusively formation of the N-ethyl-substituted compound 3b then at least a higher yield than in the preceding
example. None the less chromatographic analysis of the composition of the reaction mixture obtained showed
that the corresponding 2-ethoxy isomer 4b is formed and its yield proved even slightly higher (31%) than in the
case of the 4-methyl derivative.
The 4-amino-substituted ester also exists in the crystal exclusively in the 1,2-dihydro form [11].
However its reaction with octyl bromide in the system DMF/K2CO3 gives a mixture of N- and O-alkylation
products moreover with a predominance of the aromatic 2-alkoxy derivative [3]. One of the reasons for this
result would be a consequence of the rather large size of the alkyl group in the octyl bromide. However, after
alkylation of ethyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (1c) by ethyl iodide in the same
conditions only traces of the N-ethyl-substituted isomer 3c were found.
1297

Fig. 1. Structure of the ester 1b molecule with atomic numbering.
TABLE 1. Bond Lengths (l) in the Ester 1b Structure
Bond
l, Å
Bond
l, Å
Cl(1)–C(7)
N(1)–C(1)
1.730(3)
1.375(4)
1.206(5)
1.472(9)
1.206(5)
1.464(9)
1.396(4)
1.360(5)
1.358(5)
1.430(4)
1.456(4)
N(1)–C(9)
O(1)–C(9)
1.349(4)
1.242(4)
1.314(7)
1.507(9)
1.322(8)
1.51(1)
O(2A)–C(10)
O(3A)–C(11A)
O(2B)–C(10)
O(3B)–C(11B)
C(1)–C(6)
O(3A)–C(10)
C(11A)–C(12A)
O(3B)–C(10)
C(11B)–C(12B)
C(1)–C(2)
1.406(4)
1.395(5)
1.404(4)
1.354(4)
1.492(4)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
C(8)–C(9)
C(8)–C(10)
TABLE 2. Valence Angles (ω) in the Ester 1b Structure
Angle
ω, deg.
Angle
ω, deg.
C
(9)–N(1)–C(1)
124.8(2)
105.5(9)
102(1)
C(10)–O(3A)–C(11A)
111.3(8)
124(1)
O(3A)–C(11A)–C(12A)
O(3B)–C(11B)–C(12B)
N(1)–C(1)–C(2)
C(3)–C(2)–C(1)
C(10)–O(3B)–C(11B)
N(1)–C(1)–C(6)
C(6)–C(1)–C(2)
C(2)–C(3)–C(4)
C(4)–C(5)–C(6)
C(1)–C(6)–C(7)
C(8)–C(7)–C(6)
C(6)–C(7)–Cl(1)
C(7)–C(8)–C(10)
O(1)–C(9)–N(1)
N(1)–C(9)–C(8)
O(2B)–C(10)–O(3B)
O(2B)–C(10)–C(8)
O(3B)–C(10)–C(8)
120.6(3)
120.1(3)
120.7(3)
120.7(3)
115.9(3)
122.8(3)
118.3(2)
122.6(3)
121.5(3)
115.9(3)
124(1)
119.3(3)
119.5(3)
120.3(3)
118.6(3)
125.5(3)
118.9(2)
120.0(2)
117.3(3)
122.6(3)
125(1)
C(5)–C(4)–C(3)
C(1)–C(6)–C(5)
C(5)–C(6)–C(7)
C(8)–C(7)–Cl(1)
C(7)–C(8)–C(9)
C(9)–C(8)–C(10)
O(1)–C(9)–C(8)
O(2A)–C(10)–O(3A)
O(2A)–C(10)–C(8)
O(3A)–C(10)–C(8)
124(1)
122(1)
110.3(6)
113.3(7)
1298

Hence from the results of the investigation given it follows that the structural features of the 1H-2-oxo-
1,2-dihydroquinoline-3-carboxylate esters determined by X-ray analysis unfortunately give little information
regarding a prediction of the direction of alkylation. Such a reaction needs an initial ionization of the N–H bond
which is achieved by the addition of base and solvent. The anions of general formula 2 formed in this way have
an ambident nature. Hence the actual ratio of the N- and O-alkylated isomers via their subsequent alkylation
depends on the tautomeric equilibrium in the anion itself and it appears that it differs markedly from that in the
neutral molecule in most cases.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury VX-200 (200 MHz) instrument with DMSO-d6 as
solvent and TMS as internal standard. Chromatographic mass spectrometric work was carried out on a Varian
1200L instrument in the full scanning mode in the range 35-700 m/z with electron impact ionization 70 eV, a
CP-SIL 8CB chromatographic column of length 50 m and internal diameter 0.25 mm, a polysiloxane film coated
phase (5% diphenylpolysiloxane, 95% dimethylpolysiloxane) of thickness 0.33 µm, gas carrier helium, injector
temperature 300°C, and ion source temperature of 250°C. The synthesis of ethyl 4-chloro-1-ethyl-2-oxo-1,2-
dihydroquinoline-3-carboxylate (3b) has been reported in [12].
Ethyl 1-Ethyl-4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (2a). Iodoethane (0.89 ml, 0.011
mol) was added to a mixture of ethyl 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (1a, 2.31 g, 0.01 mol)
and K2CO3 (2.76 g, 0.02 mol) in DMF (20 ml) and stirred for 5 h at 90°C. The product was cooled and diluted
with water. The precipitate formed was extracted with dichloromethane (3 × 20 ml). The organic extracts were
combined, the solvent distilled off, and the residue was subjected to mass spectrometric analysis. For separation
of the alkylation products formed the reaction mixture was treated with hexane (3 × 15 ml). Ether (30 ml) was
added to the insoluble residue. The precipitate (starting NH-ester 1a) was filtered off, washed with ether, and
dried to give the ester 1a (0.046 g, 2%). The ether extract was purified using carbon and the solvent was distilled
off to give the N-ethyl-substituted ester 2a (1.63 g, 63%); Rf 0.23 (Silufol UV-254, Et2O–hexane, 2:1), mp 72-
74°C (aqueous ethanol). Mass spectrum, m/z (Irel, %): 259 [M]+ (22), 258 [M-H]+ (8), 230 [M-C2H5]+ (8), 214
[M-OEt]+ (53), 185 [M-OEt-C2H5]+ (80), 157 [M-OEt-C2H5-CO]+ (100), 143 (39), 130(55), 103 (40), 77 (30). 1H
NMR spectrum, δ, ppm (J, Hz): 7.90 (1H, d, J = 8.1 H-5); 7.69 (1H, td, J = 7.9 and 1.3, H-7); 7.61 (1H, d, J =
8.3, H-8); 7.33 (1H, td, J = 7.2 and 1.5, H-6); 4.29 (4H, m, NCH2 + OCH2); 2.39 (3H, s, 4-CH3); 1.28 (3H, t, J =
7.0, OCH2CH3); 1.19 (3H, t, J = 7.1, NCH2CH3). Found, %: C 69.62; H 6.78; N 5.53. C15H17NO3. Calculated,
%: C 69.48; H 6.61; N 5.40.
Ethyl 2-Ethoxy-4-methylquinoline-3-carboxylate (3a). The hexane extract remaining after removal of
the N-ethyl-substituted ester 2a (see above example) was purified using carbon and then the solvent was
removed to give the 2-ethoxy derivative 3a (0.57 g, 22%) as a colorless oily liquid with Rf 0.80 (Silufol UV-254,
Et2O–hexane, 2:1). Mass spectrum m/z (Irel, %): 259 [M]+ (12), 244 [M-CH3]+ (9), 230 [M-C2H5]+ (11), 214
1
[M-OEt]+ (27), 186 [M-OEt-CO]+ (100), 159 (66), 143 (83), 130 (27), 103 (15), 77 (20). H NMR spectrum,
δ, ppm (J, Hz): 8.00 (1H, d, J = 8.3, H-5); 7.79-7.62 (2H, m, H-7,8); 7.47 (1H, t, J = 7.2, H-6); 4.41 (4H, m,
NCH2 + OCH2); 2.55 (3H, s, 4-CH3); 1.31 (6H, m, OCH2CH3 + NCH2CH3). Found, %: C 69.66; H 6.54; N 5.35.
C15H17NO3. Calculated, %: C 69.48; H 6.61; N 5.40.
Alkylation of Ethyl 4-Chloro- (1b) and 4-Amino- (1c) 2-oxo-1,2-dihydroquinoline-3-carboxylates
using ethyl iodide was carried out similarly without preparative separation of the N- and O-alkyl isomers.
Known N-ethyl esters 3b,c were used as references for mass spectrometric investigation.
X-ray Analysis. Crystals of the ester 1b obtained from ethanol were triclinic. At 20°C: a = 6.967(3), b =
7.397(3), c = 11.526(5) Å; α = 76.18(3), β = 85.99(4), γ = 81.17(3)°; V = 569.6(4) Å3; dcalc = 1.467 g/cm3; space
–
group P1 ; Mr = 251.66; Z = 2; µ(MoKα) = 0.330 mm-1; F(000) = 60. The unit cell parameters and
1299

intensities of 3214 reflections were measured on a Siemens P3/PC, four circle automatic diffractometer
(λMoKα, graphite monochromator, θ/2θ scanning to 2θmax = 60°).
Treatment of the experimental data was carried out by the Blessing method [13]. The structure was
solved by a direct method using the program package SHELXTL [14]. For refinement of the structure, limits
2
2
3
3
were set on the bond lengths in the randomized fragment: Csp =O 1.210, Csp –O 1.33, O–Csp3 1.45, and Csp –Csp
1.52 Å. The positions of the hydrogen atoms were revealed in electron density difference synthesis and for the
randomized fragment were calculated geometrically and refined using the "riding" method with Uiso = nUeq for a
non hydrogen atom bonded to the given hydrogen (n = 1.5 for methyl groups and n = 1.2 for remaining
hydrogen atoms). The structure was refined in a full matrix least squares analysis for F2 in the anisotropic
approximation to wR2 = 0.186 for 2923 reflections (Ri = 0.077 for 1765 reflections with F > 4σ (F), S = 1.060).
The full crystallographic data has been deposited in the Cambridge structural database (register no. CCDC
283293). Interatomic distances and valence angles are given in Tables 1 and 2.
Ethyl 4-Amino-1-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (3c) was prepared by a known
method [3]. Yield 75%; mp 200-202°C (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 8.16 (1H, d, J = 8.1, H-5);
8.01 (2H, s, 4-NH2); 7.64 (1H, t, J = 7.8, H-7); 7.43 (1H, d, J = 8.6, H-8); 7.21 (1H, t, J = 7.5, H-6); 4.28-4.08
(4H, m, NCH2 + OCH2); 1.25 (3H, t, J = 7.1, CH3); 1.12 (3H, t, J = 6.9, CH3). Mass spectrum (direct
introduction), m/z (Irel, %): 260 [M]+ (74), 259 [M-H]+ (54), 232 [M-CO]+ (23), 214 [M-EtOH]+ (22), 213
[M-H-EtOH]+ (51), 188 [M-COOEt]+ (40), 187 [M-H-COOEt]+ (36), 171 (37), 158 (100), 131 (33), 116 (46),
104 (82), 77 (76). Found, %: C 64.51; H 6.32; N 10.84. C14H16N2O3. Calculated, %: C 64.60; H 6.20; N 10.76.
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