A convenient selective N-alkylation of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid

Article abstract of DOI:10.1055/s-2001-14588

The selective N-alkylation of 4-oxo-1,4-dihydro-2-quinoline carboxylic acid has been achieved from 1,2-dihydro[1,4]oxazino [4,3-a]quinoline-4,6-dione by the 2-morpholinone ring opening. In the same time, we have developed a new methodology to obtain the 1,2-dihydro[1,4]oxazino[4,3-a]quinoline-4,6-dione that involves an intramolecular cyclization of the 2-chloroethyl 6-fluoro-4-oxo-1,4-dihydro-2-quinoline carboxylate.

Full text of DOI:10.1055/s-2001-14588

LETTER
833
A Convenient Selective N-Alkylation of 4-Oxo-1,4-dihydro-2-quinoline
Carboxylic Acid
Dolorès Edmont, Jacques Chenault*
Institut de Chimie Organique et Analytique, Université d’Orléans, B.P. 6759, 45067 Orléans Cedex 2, France
Fax +33 2 3841-7281; E-mail: jacques.chenault@univ-orleans.fr
Received 1 March 2001
The starting synthon 1 was obtained by condensation of
dimethyl acetylene dicarboxylate with 4-fluoroaniline,
followed by a cyclization in diphenylether at reflux, as de-
scribed in a previous paper.3 The intermediate7 2-chloro-
Abstract: The selective N-alkylation of 4-oxo-1,4-dihydro-2-quin-
oline carboxylic acid has been achieved from 1,2-dihydro[1,4]ox-
azino[4,3-a]quinoline-4,6-dione by the 2-morpholinone ring
opening. In the same time, we have developed a new methodology
to obtain the 1,2-dihydro[1,4]oxazino[4,3-a]quinoline-4,6-dione ethyl 6-fluoro-4-oxo-1,4-dihydro-2-quinoline carboxyl-
that involves an intramolecular cyclization of the 2-chloroethyl
6-fluoro-4-oxo-1,4-dihydro-2-quinoline carboxylate.
ate 2, was obtained by a simple transesterification with
chloroethanol and a catalytic amount of sulfuric acid
(Scheme 2). The intramolecular cyclization8 of 2 was
Key words: N-alkylation, heterocycles, quinolines, ring-opening,
intramolecular cyclization
achieved in good yield using potassium carbonate in DMF
at 100 °C. The structure of the tricyclic compound 3 has
1
13
been confirmed by H and C NMR data of an identical
structure 7,8,9,10-tetrafluoro-1,2-dihydro[1,4] oxazi-
no[4,3-a]quinoline-4,6-dione obtained by Saloutin et al.9
from ethyl pentafluorobenzoyl pyruvate (3 steps with an
overall yield of 14%).
Quinolones, more known for their antibacterial activity,
sometimes display hypoglycaemic activity. Indeed, ac-
cording to Baker and Bramhall1 in 1972, these molecules
act on the glucose metabolic pathway.
Recent work2 has clearly shown the efficacy of some qui-
nolones for inhibiting the activity of the ATP-K+ channel
of the cell pancreatic membrane, thereby inducing the
production of insulin. These quinolones act according to a
mechanism similar to that found with sulfonylureas.
Using this method, we have optimized a new synthesis for
1,2-dihydro[1,4]oxazino[4,3-a] quinoline-4,6-dione; the
route requires 4 steps from commercially available ary-
lamines and the desired product is obtained with a yield
three times that of existing methods (46%).
The introduction of the carbonylguanidine moiety was
also envisaged based on ring opening of 3 with guanidine.
However, even after refluxing for 72 hours, the nucleo-
philic substitution did not take place, with the starting ma-
terial 3 being recovered unchanged (Scheme 3).
Recently, we reported the in vivo activities of some quin-
olinoylguanidines,3 and encouraged by these promising
results, we therefore decided to investigate the structure /
activity relationships of the N-[(2-quinolin)carbon-
yl]guanidines. We were interested in the selective intro-
duction of a functional group at the nitrogen atom of
4-oxo-1,4-dihydro-2-quinoline carboxylic acid.
Since the 2-morpholinone ring of 3 was opened during sa-
ponification and recyclized under acidic conditions, it was
possible to isolate the ring-opened form by addition of an
excess of benzylbromide to the reaction mixture, followed
by acidification with aqueous hydrochloric acid 3 N. This
led to the selective introduction of an N-[2-(benzyloxy)]
ethyl group10 onto the quinoline nitrogen atom. An
esterification11 using iodoethane and potassium carbonate
in DMF, followed by reaction with guanidine,12 gave the
desired N-[(2-quinolin)carbonyl]guanidine13 compound
5, isolated as its hydrochloride salt.
Historically N-alkyl quinoline-2-carboxylic acids have
been obtained from N-alkyl anilines, using the method of
Conrad and Limpach,4 or from 2-amino acetophenones
and derivatives, by condensation with diethyl oxalate us-
ing ethoxide as the base.5 Nevertheless, these two meth-
ods only provide routes to derivatives with alkyl
substituents such as isoamyl, propyl or ethyl because of
the chemistry involved in the synthesis of the quinolinic
skeleton and moderate yields are often obtained.
Previously, by using standard alkylation methodology of
the quinoline ring using sodium hydride and iodomethane,
Jaen et al.6 obtained a mixture of N-alkylated and O-alky-
lated products in 22% and 78% yield, respectively. This
reaction revealed that a competitive alkylation takes place
due to the prototropic equilibrium shown in Scheme 1.
The key to the successful synthesis of these new N-alky-
lated quinolines lies in the preparation of the 8-fluoro-1,2-
dihydro[1,4]oxazinoquinoline-1,4-dione 3 (Scheme 2).
Scheme 1
Synlett 2001 No. 6, 833–835 ISSN 0936-5214 © Thieme Stuttgart · New York

834
D. Edmont, J. Chenault
LETTER
(3) Edmont, D.; Rocher, R.; Plisson, Ch.; Chenault, J. Bioorg.
Med. Chem. Lett. 2000, 10, 1831-1834.
(4) Jones, G. Quinolines, in: Jones, G. Eds. The Chemistry of
Heterocyclic Compounds, Vol. 32, Part 1, John Wiley: New
York, 1977; pp. 143.
(5) Coltman, S. C. W.; Eyley, S. C.; Raphael, R. A. Synthesis
1984, 150-152. Cairns, H.; Cox, D.; Gould, K. J.; Ingall, A.
H.; Suschitzky, J. L. J. Med. Chem. 1985, 28, 12, 1832-1842.
(6) Jaen, J. C.; Laborde, E.; Bucsh, R. A.; Caprathe, B. W.;
Sorenson, R. J.; Fergus, J.; Spiegel, K.; Marks, J.; Dickerson,
M. R.; Davis, R. E. J. Med. Chem. 1995, 38, 22, 4439-4445.
(7) Typical experimental procedure for the transesterification: 3 g
(13.57 mmol) of 1 in 50 mL of chloroethanol and 2 mL of
sulfuric acid were stirred under reflux overnight. After
evaporation of the solvent under vacuum, the residue was
washed with water, filtered and dried under vacuum. 1H NMR
(250 MHz, DMSO-d6) 12.24 (s, 1H, NH), 7.99 (dd, 1H,
J = 5.0, 9.0 Hz, H-8), 7.69 (dd, 1H, J = 9.0, 3.0 Hz, H-5), 7.62
(ddd, 1H, J = 9.0, 10.0, 3.0 Hz, H-7), 6.70 (s, 1H, H-3), 4.60
Scheme 2 i) chloroethanol, sulfuric acid (cat), 77%; ii) K2CO3,
DMF, 100 °C, 72%.
(t, 2H, J = 5.0 Hz, OCH2), 3.96 (t, 2H, J = 5.0 Hz, CH2Cl). 13
C
NMR (62.89 MHz, DMSO-d6) 44.94, 68.83, 111.07, 111.46,
124.47, 129.12, 140.21, 141.14, 161.67, 164.68, 166.03,
178.01. Mass spectrum m/z (ionspray ): 270 (M+, 100%), 272
(M++2, 30%).
(8) Typical experimental procedure for the intramolecular
cyclization: To a solution of 5.8 g of 2 in 174 mL of DMF, was
added 3.4 g of potassium carbonate and the reaction mixture
was stirred at 100 °C during 4 hours. After evaporation of the
solvent, the residue was acidified with HCl 3 N and
Scheme 3 iii) DMF, guanidine; iv) a NaOH 6 N, benzyl bromide,
reflux; b HCl 3 N, 50%; v) a DMF, K2CO3, EtI, 50 °C, 89%; b DMF,
guanidine, 24 h; c HCl 3 N, 62%; vi) a DMF, MeONa, 50 °C; b HCl
3 N, 79%; vii) a DMF, K2CO3, EtI, 50 °C, 76%; b DMF, guanidine,
24 h; c HCl 3 N, 72%.
concentrated. The residue was dissolved in DMF, inorganic
salts filtered and the DMF evaporated. Compound 3 was then
filtered and washed with acetonitrile. 1H NMR (250 MHz,
DMSO-d6) 7.95 (dd, 1H, J = 5.0, 9.0 Hz, H-8), 7.74-7.83 (m,
2H, H-5 and H-7), 6.74 (s, 1H, H-3), 4.76 (t, 2H, J = 5.0 Hz,
OCH2), 4.48 (t, 2H, J = 5.0 Hz, NCH2). 13C NMR (62.89 MHz,
DMSO-d6) 42.32, 64.95, 109.40, 110.87, 120.15, 121.91,
127.93, 136.35, 137.31, 158.95, 159.85, 175.33. Mass
spectrum m/z (ionspray ): 234 (MH+, 100%).
We also introduced an N-vinylic group onto the quinoline
nitrogen atom. The synthesis of 6 was developed based on
ring opening of 3 with sodium methoxide.14 The forma-
tion of this new compound 6 may be explained by a depro-
tonation at the alpha position to the nitrogen atom. As for
compound 4, an esterification11 of 6, followed by reaction
with guanidine,12 gave compound 7.13
(9) Saloutin, V. I.; Skryabina, Z. E.; Basyl’, I. T.; Kondrat’ev, P.
N.; Chupakhin, O. N. J. Fluorine Chem. 1994, 69, 119.
(10) Procedure for 4: 1.5 g of 3 in 13 mL of NaOH 6 N and 2.3 mL
of benzyl bromide were stirred under reflux overnight. The
reaction mixture was then acidified at 0 °C, and filtered. The
precipitate was washed with water and diethyl ether. 1H NMR
(250 MHz, DMSO-d6) 7.98 (dd, 1H, J = 4.0, 9.0 Hz, H-8),
7.78 (dd, 1H, J = 9.0, 3.0 Hz, H-5), 7.62 (ddd, 1H, J = 9.0, 9.5,
3.0 Hz, H-7), 7.07-7.18 (m, 5H, Harom), 6.35 (s, 1H, H-3), 4.71
(t, 2H, J = 5.0 Hz, OCH2), 4.35 (s, 2H, OCH2Ar), 3.64 (t, 2H,
J = 5.0 Hz, NCH2). 13C NMR (62.89 MHz, DMSO-d6) 48.51,
68.09, 72.77, 110.33, 110.43, 122.00, 122.07, 127.87, 128.01,
128.92, 129.10, 138.17, 138.70, 147.64, 159.48, 165.87,
176.35. Mass spectrum m/z (ionspray ): 342 (MH+, 100%).
(11) Typical procedure for the esterification: To a solution of 1
equiv of the acid in 2 mL of DMF, was added 3 equiv of
potassium carbonate and the reaction mixture was stirred at
room temperature during 1 hour. Then 0.2 mL of iodoethane
was added and the reaction mixture was heated at 50 °C
during 4 hours. After evaporation of the solvent, the crude
product was extracted into CH2Cl2, which was washed with
water, dried (MgSO4) and evaporated. Purification was done
by column chromatography (CH2Cl2).
In summary, we have selectively alkylated the nitrogen
atom of a 2-quinoline carboxylic acid via the ring opening
of the 8-fluoro-1,2-dihydro [1,4]oxazino[4,3-a]quinoline-
4,6-dione. The introduction of these two new functional
groups, N-[2-(benzyloxy)]ethyl and N-vinyl, offer routes
to a wide variety of further analogues in order to perform
some structural modifications within the framework of
our SAR studies. In addition, we have developed a new
route to 1,2-dihydro [1,4]oxazino[4,3-a]quinoline-4,6-di-
one in 4 steps from commercially available arylamines
with an overall yield of 46%. We are currently studying
the 2-morpholinone-ring opening reaction using nucleo-
philic, electrophilic or reducing agents.
References and Notes
(12) Typical procedure for the guanylation: To a solution of 1
equiv of the ester in 2.5 mL of DMF, was added 5 equiv of
guanidine. After 24 hours at room temperature, the reaction
mixture was added to 100 mL of cold water. The precipitate
was then filtered, washed with water and dried under vacuum.
(1) Baker, B. R.; Bramhall, R. J. Med. Chem. 1972, 15, 233.
(2) Maeda, N.; Tamagawa, T.; Niki, I.; Miura, H.; Ozawa, K.;
Watanabe, G.; Nonogaki, G.; Uemura, K.; Iguchi, A. Br. J.
Pharmacol. 1996, 117, 372.
Synlett 2001, No. 6, 833–835 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Convenient Selective N-Alkylation
835
(13) The both new N-[(2-quinolin)carbonyl]guanidine 5 and 7 have
been fully characterized by mp, IR, MS or 1H and 13C NMR
spectra. The purities were found to be satisfactory for the
pharmacological tests.
(14) Procedure for 6: To a solution of 1 g of 3 in 9 mL of DMF, was
added 400 mg of MeONa and the reaction mixture was then
stirred for 3 hours at room temperature. The solvent was
removed under vacuum and the residue was acidified with
HCl 3 N. The precipitate was filtered, washed with water and
dried under vacuum. 1H NMR (250 MHz, DMSO-d6) 7.77
(dd, 1H, J = 9.1, 3.14 Hz, H-5), 7.71 (dd, 1H, J = 4.71, 9.42
Hz, H-8), 7.58 (ddd, 1H, J = 9.42, 3.14, 9.16 Hz, H-7), 7.24
(dd, 1H, J = 15.07, 7.54 Hz, CH), 6.32 (s, 1H, H-3), 5.63 (dd,
1H, J = 7.54, 1.0 Hz, CH2), 5.47 (dd, 1H, J = 15.07, 1.0 Hz,
CH2). 13C NMR (62.89 MHz, DMSO-d6) 108.57, 109.41,
118.60, 120.89, 121.35, 126.78, 134.43, 136.96, 145.55,
158.78, 164.04, 175.71. Mass spectrum m/z (ionspray ): 234
(M+, 100%).
Article Identifier:
1437-2096,E;2001,0,06,0833,0835,ftx,en;D05101ST.pdf
Synlett 2001, No. 6, 833–835 ISSN 0936-5214 © Thieme Stuttgart · New York