Synthesis of 2-aryl-oxazolo[4,5-c]quinoline-4(5H)-ones and 2-aryl-thiazolo[4,5-c]quinoline-4(5H)-ones

Article abstract of DOI:10.1021/ol0350285

(Matrix presented) Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively,

Full text of DOI:10.1021/ol0350285

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2911-2914
Synthesis of
2-Aryl-oxazolo[4,5-c]quinoline-4(5H)-ones
and
2-Aryl-thiazolo[4,5-c]quinoline-4(5H)-ones
Kevin J. Hodgetts* and Mark T. Kershaw
Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405
khodgetts@nrgn.com
Received June 8, 2003
ABSTRACT
Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl
2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively, are described.
In the search for biologically active compounds as potential
drug candidates, the efficient synthesis of both libraries and
individual heterocyclic small molecules is of major impor-
tance to the pharmaceutical industry. Approaches involving
a sequence of regiocontrolled halogenation followed by
palladium-catalyzed coupling based upon a heterocyclic
scaffold have been successfully developed.1 We have previ-
ously described the regiocontrolled synthesis of substituted
thiazoles2 and oxazoles3 using such a strategy. As part of a
medicinal chemistry project at Neurogen, a series of 2-aryl-
oxazolo[4,5-c]quinoline-4(5H)-ones (1) having high affinity
for the GABA (γ-aminobutyric acid) receptor were discov-
ered.4,5 GABA is a major inhibitory neurotransmitter in the
central nervous system, and compounds with the appropriate
receptor binding profile and functional selectivity have
potential pharmaceutical use as anxiolytics, hypnotics, and
cognition enhancers.6 Routes to oxazolo[4,5-c]-quinolinones
reported in the literature include (i) cyclization of 3-amino-
4-hydroxy-2-quinolones with carboxylic acids in polyphos-
phoric acid (PPA),7 (ii) Beckmann rearrangement of the
oxime of 3-aryl-4-hydroxy-2-quinolones,8 (iii) reaction of
isatoic anhydrides with R-isocyanoacetates,9 and (iv) ther-
molysis of 4-azidoquinolones with carboxylic acids in PPA.10
Limitations to these approaches include the preparation and
the reported instability of the 3-amino-4-hydroxy-2-quinolone
intermediates11 and the relatively harsh cyclization conditions,
(6) For recent reviews of the therapeutic areas addressed through
modulation of GABA, see: (a) Chebib, M.; Johnston, G. A. R. J. Med.
Chem. 2000, 43, 1427. (b) Tallman, J. F.; Cassella, J. V.; White, G.;
Gallagher, D. W. Neuroscientist 1999, 5, 351.
(7) (a) Merchant, J. R.; Shirali, S. S. Bull. Chem. Soc. Jpn. 1977, 50,
3075. (b) Ponomarev, O. A.; Brusilt’sev, Y. N.; Grif, V. K.; Mitina, V. G.
Ukr. Khim. Zh. 1990, 56, 272. (c) Ukrainets, I. V.; Taran, S. G.; Sidorenko,
L. V.; Gorokhova, O. V.; Turov, A. V. Chem. Het. Compds. 1997, 33,
1328.
(8) Zoorob, H. H.; Hamama, W. S. Egypt. J. Chem. 1986, 29, 325.
(9) Suzuki, M.; Matsumoto, K.; Miyoshi, M.; Yoneda, N.; Ishida, R.
Chem. Pharm Bull. 1977, 25, 2602.
(10) Steinschifter, W.; Fiala, W.; Stadlbauer, W. J. Het. Chem. 1994,
31, 1647 and references therein.
(1) For excellent reviews of this strategy see: (a) Collins, I. J. Chem.
Soc., Perkin Trans. 1 2002, 1921. (b) Collins, I. J. Chem. Soc., Perkin Trans.
1 2000, 2845. (c) Snieckus, V. Med. Res. ReV. 1999, 19, 342.
(2) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 1363.
(3) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905.
(4) Albaugh, P. U.S. Patent 5,182,290, 1993.
(5) For related series, see: (a) Albaugh, P. A.; Marshall, L.; Gregory,
J.; White, G.; Hutchison, A.; Ross, P. C.; Gallagher, D. W.; Tallman, J. F.;
Crago, M.; Cassella, J. V. J. Med. Chem. 2002, 45, 5043. (b) Forbes, I. T.;
Johnson, C. N.; Jones, G. E.; Loudon, J.; Nicholass, J. M. Thompson, M.
J. Med. Chem. 2002, 45, 2640 and references therein.
(11) Ukrainets, I. V.; Taran, S. G.; Sidorenko, L. V.; Gorokhova, O. V.;
Turov, A. V.; Ogirenko, A. A. Chem. Heterocycl. Compd. 1997, 33, 815.
10.1021/ol0350285 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/08/2003

heating to 120-150 °C in PPA, which are incompatible with
sensitive functionality. We were also interested in the
synthesis of the related thiazolo analogues, although to the
best of our knowledge thiazolo[4,5-c]-quinoline-4(5H)-ones
(2) have not previously been reported in the chemical
literature.
should be possible via a palladium-catalyzed Heck13 reaction
of a 2-haloaniline 3 and the 5-position of the oxazole
(disconnection b).14 Cyclization between the aniline and the
4-carboxyl functionality of the oxazole should complete the
synthesis of 1 (disconnection c). Reversing the order of the
disconnections b and c, amide bond formation followed by
intramolecular Heck reaction, should also lead to 1.
The 2-phenyl substituent was introduced by Suzuki-
Miyaura15 coupling of the oxazole 4 with phenylboronic acid
and gave 6 in 87% yield. The introduction of the second
aryl group at the 5-oxazole position via a palladium-catalyzed
Heck reaction13 was then investigated. Optimal conditions
for 2-iodonitrobenzene proved to be Pd(OAc)2, PPh3, and
Cs2CO3 in DMF at 140 °C for 3 h, which gave an 83% yield
of the coupled product 7. To widen the breadth of potential
aryl substituents, 2-bromo- and 2-chloronitrobenzene were
also examined in the reaction. Under the same conditions
2-bromonitrobenzene gave clean coupling and an excellent
80% yield of 7, whereas 2-chloronitrobenzene gave a modest
31% yield. Aryl chlorides are generally very poor electro-
philes in the Heck reaction; however, the electron-withdraw-
ing nitro substituent enhances the rate of the oxidative
addition step during the catalytic cycle. Heating the reaction
longer than 3 h did not increase the yield of 7 presumably
because of palladium complex decomposition. To prolong
the life of palladium complexes, PPh3 ligands have been
replaced by the more bulky P(o-tolyl)3, the assumption being
that the bulkier phosphine forms a more stable PdL2 species
and that quaternization of the phosphorus by the aryl halide
is minimized.16 Gratifyingly, the use of P(o-tolyl)3 in place
of PPh3 in the reaction of 4 with 2-chloronitrobenzene gave
a 78% yield of 7. The nitro group of 7 was then hydroge-
nated, using 10% Pd/C as the catalyst, and gave following
workup, somewhat surprisingly, only the uncyclized aniline
8. Indeed, the 1H NMR of a d6-DMSO solution of the aniline
8 remained unchanged after several hours at room temper-
ature. To complete the cyclization, the aniline 8 was refluxed
in a solution of DME and aqueous K2CO3 and gave,
following recrystallization, pure 2-phenyl-oxazolo[4,5-c]-
quinoline-4(5H)-one (9)7c in 77% yield (Scheme 2).
Figure 1.
We required efficient and flexible routes, such that
modifications at the 2-position and on the A-ring could easily
be accomplished. Three disconnections, a, b, and c, indicated
that 1 could be constructed from readily available starting
materials: 2-haloaniline 3, ethyl 2-chlorooxazole-4-carboxy-
late (4),3 an organometallic reagent 5 and a sequence of
palladium-catalyzed reactions (Scheme 1). We have previ-
Scheme 1
An alternative method for the introduction of the 5-aryl
substituent was investigated next. The oxazole 6 was
brominated at the 5-position by treatment with an excess of
N-bromosuccinimide in refluxing chloroform and gave the
bromide 10 in 86% yield. Under Suzuki-Miyaura conditions
the 5-bromooxazole 10 was treated with commercially
ously established that a variety of substituents could be
incorporated at the 2-position of the oxazole 43 using various
palladium-catalyzed reactions (disconnection a).12 Introduc-
tion of the second aryl ring, destined to become the A-ring,
(13) For reviews, see: (a) Heck, R. F. Org. React. 1982, 27, 345-390.
(b) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. For
mechanistic insight, see: (c) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427.
(d) Amatore, C.; Jutland, A. Acc. Chem. Res. 2000, 33, 314.
(12) For other examples of palladium-catalyzed reactions of oxazoles,
see: (a) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry;
Pergamon Press: Elmsford, Oxford, 2000; Chapter 8, pp 321-333. (b)
Sakamoto, T.; Nagata, H.; Kondo, Y.; Shiraiwa, M.; Yamanaka, H. Chem.
Pharm. Bull. 1987, 35, 823. (c) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995,
415. (d) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4633. (e) Jeong, S.;
Chen, X.; Harran, P. G. J. Org. Chem. 1998, 63, 8640. (f) Boto, A.; Ling,
M.; Meek, G.; Pattenden G. Tetrahedron Lett. 1998, 39, 8167. (g) Vedejs,
E.; Luchetta, L. M. J. Org. Chem. 1999, 64, 1011. (h) Schaus, J. V.; Panek,
J. S. Org. Lett. 2000, 2, 469. (i) Smith, A. B., III; Minibiole, K. P.; Verhoest,
P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942. (j) Clapham, B.;
Sutherland, A. J. J. Org. Chem. 2001, 66, 9033.
(14) For an example of a Heck reaction at the 5-position of an oxazole,
see: (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467. For other heteroaryl Heck reactions,
see: (b) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko,
M. F. Org. Lett. 2003, 5, 301. (c) McClure, M. S.; Glover, B.; McSorley,
E.; Maillar, A.; Osterhout, M. H.; Roschangar, F. Org. Lett. 2001, 3, 1677.
(d) Hii, K. K.; Claridge, T. D. W.; Brown, J. M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 984. (e) Itahara, T. J. J. Org. Chem. 1985, 50, 5272.
(15) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem ReV. 1995,
95, 2457. (b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633.
(16) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941.
2912
Org. Lett., Vol. 5, No. 16, 2003

Scheme 2a
Scheme 4a
a Reaction conditions: (i) NaOH, EtOH, rt (89%); (ii) BOP,
2-IC6H4NH2, Et3N, CH2Cl2, rt (78%); (iii) Pd(OAc)2, PPh3, Cs2CO3,
DMF, 140 °C (63%).
a Reaction conditions: (i) PhB(OH)2, Pd(PPh3)4, PhMe, H2O,
K2CO3, 90 °C (87%); (ii) 2-IC6H4NO2, Pd(OAc)2, PPh3, Cs2CO3,
DMF, 140 °C (83%); (iii) 10% Pd/C, MeOH, H2; (iv) DME, H2O,
K2CO3, reflux (77%).
sodium hydroxide and gave the acid 11 in 89% yield. BOP18
coupling of the acid 11 with 2-iodoaniline gave the amide
12 in 78% yield. Exposure of the iodide 12 to the Heck
conditions described earlier gave cyclization to 9 in 63%
isolated yield, although no attempts were made to optimize
the conditions of this reaction.
The wide range of organometallic reagents available for
the introduction of the 2-substituent and the large array of
compatible reagents for installation of the aryl group at the
oxazole 5-position (destined to become the A-ring) offer
considerable flexibility for the synthesis of substituted
oxazolo[4,5-c]quinoline-4(5H)-ones from a single precursor,
ethyl 2-chlorooxazole-4-carboxylate (4).
available 2-aminophenylboronic acid, which presumably
gave the 5-aryl oxazole 8, although on this occasion and
under the conditions of the reaction, cyclization occurred and
gave 9 in 78% yield (Scheme 3).
Scheme 3a
Thiazolo[4,5-c]-quinoline-4(5H)-ones (2) have not previ-
ously been reported in the chemical literature, and in principle
any of the approaches outlined in Schemes 2-4 could be
adapted. The most direct route proved to be the one-pot
synthesis of 2 from the readily available ethyl 2-bromo-5-
chlorothiazole-4-carboxylate (13)2,19 and consecutive pal-
ladium-catalyzed coupling reactions. Using standard Suzuki-
Miyaura conditions, the thiazole 13 was treated with 1 equiv
of 3,4-dimethoxyphenyl boronic acid at 80 °C. After 4 h
none of the starting material (13) remained by TLC. A further
5 mol % of Pd(Ph3P)4 and 1.5 equiv of commercially
available 2-aminophenyl boronic acid were added, and the
reaction was reheated to 80 °C for a further 4 h. Following
aqueous workup and recrystallization, the cyclized product
2 was isolated in 69% yield. The formation of the quinoli-
none 2 confirmed that the initial coupling was selective for
the 2-position and gave the intermediate 14 and that the
second coupling at the 5-position gave the intermediate 15
and, under the conditions of the reaction, cyclization to the
tricycle 2 (Scheme 5).
a Reaction conditions: (i) NBS, CHCl3, 60 °C (86%); (ii)
2-NH2C6H4B(OH)2, Pd(PPh3)4, DME, H2O, K2CO3, 80 °C (78%).
The palladium-catalyzed intramolecular diaryl coupling has
previously been used for the synthesis of several tricyclic
systems,17 and we chose to investigate its application to the
synthesis of 2-phenyl-oxazolo[4,5-c]quinoline-4(5H)-one (9)
(Scheme 4). To this end the ester 6 was hydrolyzed with
We have described two novel synthetic routes to 2-sub-
stituted-oxazolo[4,5-c]quinoline-4(5H)-ones (1) from the
(17) For examples, see: (a) Ames, D. E.; Opalko, A. Tetrahedron 1984,
40, 1919. (b) Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915. (c)
Hernandez, S.; SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett. 2003,
5, 1095. For a general review, see: (d) Gibson, S. E.; Middleton, R. J.
Contemp. Org. Synth. 1996, 3, 447.
(18) Castro, B.; Dormoy, J. R.; Evin, G.; Selvey, C. Tetrahedron Lett.
1975, 1219.
(19) Okonya, J. F.; Al-Obeidi, F. Tetrahedron Lett. 2002, 43, 7051.
Org. Lett., Vol. 5, No. 16, 2003
2913

also be used for this step. In the first approach, intermolecular
Heck or Suzuki-Miyaura coupling reactions were used to
introduce aryl substituents to the oxazole 5-position. The aryl
group then became the A-ring of the oxazolo[4,5-c]quinoline-
4(5H)-one (1) following cyclization. In the second approach,
an intramolecular palladium-catalyzed coupling reaction
between an aryl iodide and the oxazole 5-position was the
key step in the synthesis. The synthesis of 2-substituted-
thiazolo[4,5-c]quinoline-4(5H)-ones (2) was also described.
The one-pot introduction of both the 2-substituent and the
A-ring and subsequent cyclization from the readily available
ethyl 2-bromo-5-chloro-4-thiazole carboxylate (13), without
the need for chromatography, is noteworthy. The efficiency
of the reactions and the diversity of compatible starting
materials and reagents make the described methodologies
attractive and flexible entries into 2-substituted-oxazolo[4,5-
c]quinoline-4(5H)-ones (1) and 2-substituted-thiazolo[4,5-
c]quinoline-4(5H)-ones (2).
Scheme 5a
a Reaction conditions: (i) 3,4-(MeO)2C6H3B(OH)2, Pd(PPh3)4,
DME, H2O, K2CO3, 80 °C; then (ii) 2-NH2C6H4B(OH)2, Pd(PPh3)4,
80 °C (69%).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 4, 6-13, and
2. This material is available free of charge via the Internet
at http://pubs.acs.org.
same precursor, ethyl 2-chlorooxazole-4-carboxylate (4). In
both approaches the 2-substituent was introduced by a
Suzuk-Miyaura reaction, although we have previously
shown that a wide variety of organometallic reagents could
OL0350285
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Org. Lett., Vol. 5, No. 16, 2003