A mild and efficient synthesis of 4-quinolones and quinolone heterocycles

Article abstract of DOI:10.1021/jo070181o

(Chemical Equation Presented) The cycloacylation of aniline derivatives to 4-quinolones in the presence of Eaton's reagent is described. This high-yielding methodology is applicable to a wide variety of functionalized anilines and requires milder conditio

Full text of DOI:10.1021/jo070181o

makes it difficult to handle for large-scale operations. The lack
of a general and mild method led researchers to develop new
synthetic strategies that involve an increased number of steps,8
isolation or purification of reactive intermediates,9 and the use
of toxic reagents.8,10 These alternative strategies typically give
low yields of quinolones, making them unattractive for general
large-scale synthetic applications. It is clear that an efficient
protocol is needed.
A Mild and Efficient Synthesis of 4-Quinolones
and Quinolone Heterocycles
Daniel Zewge,* Cheng-yi Chen, Curtis Deer,†
Peter G. Dormer, and Dave L. Hughes
Department of Process Research, Merck Research Laboratories,
P.O. Box 2000, Rahway, New Jersey 07065
Herein, we describe our discovery that Eaton’s reagent,11 an
inexpensive and commercially available substance, could ef-
fectively be used to promote the cyclization of aniline derivatives
to produce 4-quinolones in high yields under mild conditions
(<90 °C). This observation has been found to be applicable to
the synthesis of a series of quinolone and heterocyclic deriva-
tives. In the context of a drug development program, we required
a robust protocol for a multi-kilogram synthesis of 1,4-dihydro-
8-methoxy-4-oxo-2-quinolone carboxylic acid, methyl ester 1b
(eq 1).
daniel_zewge@merck.com
ReceiVed February 15, 2007
The cycloacylation of aniline derivatives to 4-quinolones in
the presence of Eaton’s reagent is described. This high-
yielding methodology is applicable to a wide variety of
functionalized anilines and requires milder conditions than
those traditionally employed. This cyclization protocol is
used to prepare a host of heterocycles and bis-quinolones
and is characterized by relatively low reaction temperature
and ease of product isolation.
Our initial efforts at synthesizing 1b employed the Conrad-
Limpach protocol. We were pleased that we could obtain
quinolone 1b in 74% yield, albeit at the prohibitively high
temperature of 250 °C in diphenyl ether. The harsh reaction
conditions are needed presumably due to the cis stereochemical
relationship of the ester groups in 1a, which would require
isomerization prior to ring closure.12
With PPA as a solvent the cyclization could be performed at
140 °C; however, only 20% of the product was isolated. Given
the difficulties, we focused on identifying alternate conditions.13
Derivatives of 4-quinolone exhibit impressive antibiotic
activity1 and have been extensively investigated as antidiabetic,2
anticancer,3,4 and antiviral5 agents. Given their utility, the
development of synthetic methodology to access 4-quinolone
derivatives is continually warranted. To date, the most frequently
used strategy for their synthesis employs the Conrad-Limpach
and Gould-Jacobs cyclizations.6 These methodologies involve
thermal cyclization of aniline derivatives to 4-quinolones under
extremely harsh conditions. Reactions are typically carried out
in mineral oil, Dowtherm, or diphenyl ether at 250 °C. The harsh
reaction conditions have made synthesis and isolation of pure
products difficult. Alternatively, polyphosphoric acid (PPA)7 can
be used for similar cyclizations; however, its high viscosity
(8) (a) Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68,
2223-2233. (b) Hong, W. P.; Lee, K-J. Synthesis 2006, 963-968.
(9) Chong, R. J.; Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1986,
27, 5323-5326.
(10) Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org. Lett. 2002, 4, 4411-
4414.
(11) For reactions employing Eaton’s reagent, refer to: (a) Eaton, P. E.;
Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38, 4071-4073. (b) McGarry,
L. W.; Detty, M. R. J. Org. Chem. 1990, 55, 4349-4356. (c) Trost, B. M.;
Toste, F. D.; Greenman, K. J. Am. Chem. Soc. 2003, 125, 4518-4526. (d)
During the preparation of this manuscript, a similar transformation of an
o-iodoaniline intermediate at 90 °C using Eaton’s reagent was reported:
Dorow, R. L.; Herrinton, P. M.; Hohler, R. A.; Maloney, M. T.; Mauragis,
M. A.; McGhee, W. E.; Moeslein, J. A.; Strohbach, J. W.; Veley, M. F.
Org. Process Res. DeV. 2006, 10, 493-499. (e) Eaton’s reagent (7.7/92.3
% by weight of P2O5/ MeSO3H) was purchased from Sigma-Aldrich
(12) Gradient 1D NOESY using Gaussian excitation pulse and 500-
600 ms mixing time: (a) Kessler, H.; Oschkinat, H.; Griesinger, C.; Bermel,
W. J. J. Magn. Reson. 1986, 70, 106-133. (b) Stonehouse, J.; Adell, P.;
Keeler, J.; Shaka, A. J. J. Am. Chem. Soc. 1994, 116, 6037-6038. (c) Stott,
K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A. J. J. Am. Chem.
Soc. 1995, 117, 4199-4200. NOE summary:
† UNCF-Merck undergraduate scholarship.
(1) (a) Pazharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Hetero-
cycles in Life and Society; John Wiley & Sons: Chichester, 1997; pp 147-
148. (b) Mitscher, L. A. Chem. ReV. 2005, 105, 559-592.
(2) Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Bioorg. Med. Chem.
Lett. 2000, 10, 1831-1834.
(3) Xia, Y.; Yang, Z-Y.; Xia, P.; Bastow, K. F.; Nakanishi, Y.;
Nampoothiri, P.; Hamel, E.; Brossi, A.; Lee, K-H. Bioorg. Med. Chem.
Lett. 2003, 13, 2891-2893.
(4) Nakamura, S.; Kozuka, M.; Bastow, K. F.; Tokuda, H.; Nishino, H.;
Suzuki, M.; Tatsuzaki, J.; Natschke, S. L. M.; Kuo, S-C.; Lee, K-H. Bioorg.
Med. Chem. 2005, 13, 4396-4401.
(5) Lucero, B. d’A.; Gomes, C. R. B.; Frugulhetti, I. C. de P. P.; Faro,
L. V.; Alvarenga, L.; Souza, M. C. B. V.; de Souza, T. M. L. Ferreira, V.
F. Bioorg. Med. Chem. Lett. 2006, 16, 1010-1013.
(6) (a) Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890-
2895. (b) Heindel, N. D.; Bechara, I. S.; Kennewell, P. D.; Molnar, J.;
Ohnmacht, C. J.; Lemke, S. M.; Lemke, T. F. J. Org. Chem. 1968, 11,
1218-1221.
(13) (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb.
Chem. 2002, 4, 95-105. (b) Microwave-assisted synthesis of 1b was briefly
explored and found to give product, albeit in poor yields.
(7) Rowlands, D. A. Synth. Reagents 1985, 6, 156-414.
10.1021/jo070181o CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/26/2007
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J. Org. Chem. 2007, 72, 4276-4279

SCHEME 1. Synthesis of 4-Quinolone-2-carboxylic Acid, Methyl Esters via Cyclization Using Eaton’s Reagent
SCHEME 2. Synthesis of 4-Quinolone-3-carboxylic Acid, Methyl Esters via Cyclization Using Eaton’s Reagent
TABLE 1. Synthesis of 2-Carboxy-4-quinolones16
A variety of other acids and solvents were screened, each giving
unacceptable yield of 1b.14 We then shifted our focus to Eaton’s
reagent, a mixture of P2O5 and MeSO3H. Our preliminary
investigations on the use of this reagent for cyclization of 1a to
1b in the presence of cosolvents15 at temperatures ranging from
25 to 100 °C were not conclusive as it resulted in very low
conversion. However, we were pleased to discover that simply
dissolving 1a in Eaton’s reagent and heating to only 50 °C
resulted in quantitatiVe conVersion to 1b within 1 h. The ease
of isolation of 1b was notable as a simple quench into a saturated
basic solution precipitates the product in acceptable purity (97%
isolated yield). The importance of P2O5 in this reaction is
illustrated by the fact that substrate 1a does not give cyclized
product after heating at 50 °C over 15 h in neat MeSO3H.
Having successfully identified a facile route for large-scale
preparation of quinolone 1b, we chose to investigate the
generality of this reaction for the preparation of related
4-quinolones from aryl amines with various substituents. Enam-
ine substrates (Table 1, entries 1-9) were prepared in quantita-
tive yield via condensation of commercially available aryl
amines with dimethyl acetylenedicarboxylate (DMAD) in
alcoholic solvents at temperatures ranging from 25 to 60 °C
(Scheme 1).2
The new protocol was examined and found to be effective
for the cyclization of enamines with various types of substitu-
ents, including substrates with electron-withdrawing groups
which are typically poor substrates for similar cyclizations. In
all cases, Eaton’s reagent promoted cyclization at 50 °C and
gave high yields of 2-carboxy-4-quinolones in less than 3 h.16
The exceptional crystallinity of these products enabled facile
isolation of 4-quinolones after basic quench of the reaction
mixture. To further highlight the utility of this method the
isopropyl-substituted quinolone (Table 1, entry 6) could be
prepared in 92% yield. In Ph2O at 230 °C this product was
isolated in 44% yield.17
entry
R1
R2
R3
R4
% isolated yield
1
2
3
4
5
6
7
8
9
OMe
Cl
OMe
H
Br
i-Pr
H
H
Cl
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
Cl
H
H
H
H
H
H
98
95
94
85
95
92
90
96
90
H
CO2Me
H
C6H11
Cl
H
TABLE 2. Synthesis of 3-Carboxy-4-quinolones
entry
R1
R2
R3
R4
% isolated yield
10
11
12
Cl
H
F
H
H
H
H
OMe
F
H
H
H
96
90
94
cyclization protocol to the synthesis of these molecules. Enam-
ines (Table 2, entries 10-12), were prepared via condensation
of aryl amines with dimethyl methoxymethylenemalonate in
refluxing toluene (Scheme 2) and used without purification.
Cyclization was complete over 2-5 h and required
higher temperatures (80-90 °C) than the compounds in Table
1, a result of relative increased steric nature of these
substrates.
Encouraged by the results detailed in Tables 1 and 2, we
envisioned the application of the mild cyclization conditions to
the synthesis of tetracyclic bis-quinolones and quinolone
heterocycles (Tables 3 and 4). Structures and derivatives similar
to those shown in Table 3 have been extensively studied as
medicinal agents as well as effective proton sponges18 and may
be useful as potential ligands for transition metals. The
cyclization protocol was successfully implemented for the
preparation of bis-quinolones (Table 3, entries 13-16). All of
the products were isolated as analytically pure solids after basic
quench as described above.
As there are several 3-carboxy-4-quinolones of medicinal
interest,1,2 we focused our attention on the application of the
It is important to note that cyclization of 1,8-naphthalene
diamine derivative (Table 3, entry 15) resulted in isolation of
85% of quinolinoquinolinedione. The same transformation at
230 °C in diphenyl ether gave 58% yield of product.19 Finally,
(14) Aging a solution of 1a in H2SO4, TFA, or HOAc at 50-100 °C
over prolonged period of time resulted in the recovery of substrate 1a along
with significant amounts of hydrolysis product (aniline).
(15) The use of 1:1 and 2:1 mixtures of solvents including toluene,
xylene, and tetramethylene sulfone along with Eaton’s reagent resulted in
sluggish conversion. The best conversion obtained was 3% after 20 h at
100 °C in a 1:1 mixture of toluene and Eaton’s reagent.
(16) See the Experimental Section.
(18) (a) Zirnstein, M. A.; Staab, H. A. Angew. Chem. 1987, 99, 460-
462. (b) Hall, C. M.; Wright, J. B.; Johnson, H. G.; Taylor, A. J. J. Med.
Chem. 1977, 20, 1337-1343.
(19) Honda, K.; Nakanishi, H.; Yabe, A. Bull. Chem. Soc. Jpn. 1983,
56, 2338-2340.
(17) Kikuchi, K.; Tagami, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.;
Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2001,
11, 1215-1218.
J. Org. Chem, Vol. 72, No. 11, 2007 4277

TABLE 3. Bis-Cyclization of Diamine Derivativesa,16
TABLE 4. Synthesis of Heterocyclic Quinolones16
a Reactions were performed in 6 vol of Eaton’s reagent at 50 °C. R )
COOMe.
in order to further extend the utility of the cyclization protocol,
several heterocyclic enamines (Table 4, entries 17-26) were
prepared using identical protocols as illustrated in Schemes 1
and 2.
Gratifyingly, the cyclization protocol was applicable to the
synthesis of heterocyclic quinolones. Enamine derivatives of
aminoquinolines (Table 4, entries 23 and 24), aminobenzothia-
zoles (Table 4, entries 18 and 19), aminoindans (Table 4, entry
17), and aminothiophenes (Table 4, entries 20 and 21) were
consistently prepared in good yields. Aminopyrrole derivative
(Table 4, entry 25) gave a moderate yield of cyclized product.
It is interesting to note that the aminobenzothiazole derivatives
(Table 4, entries 18 and 19) were selectively cyclized adjacent
to the sulfur atom in the molecule,20 indicating a possible
activating effect by electrons on the sulfur atom. A derivative
of N-(4-aminobenzoyl)-â-alanine (Table 4, entry 26) gave 75%
yield of the quinolone. The alanine portion of the molecule did
not cyclize to a 7-membered ring; instead, it was converted to
an ester, likely due to the presence of MeOH byproduct in the
process. While the synthesis of thienopyridine (Table 4, entry
20) under thermal cyclization conditions (250 °C) has been
reported,21 yields obtained for the particular conversion were
not discussed.
a Reactions were performed at 50 °C in 4 vol of Eaton’s reagent.
b Reactions were performed at 90 °C in 4 vol of Eaton’s reagent. R )
COOMe.
was not regioselective and resulted in several products when
applied to a substrate derived from a meta-substituted ary-
lamine.22 An attempt to prepare a 7-membered ring keto
benzoazepin from a substrate derived from a p-methoxyaniline
and succinic anhydride was not effective. A known PPA
cyclization23 of 3-phenylpropanoic acid to generate a 5-mem-
bered ring compound (1-indanone) was also examined with
Eaton’s reagent and resulted in very little product.
(22) Aryl amines with electron donating as well as withdrawing
substituents at the meta position resulted in messy reaction profiles. An
attempt to synthesize 1,4-dihydro-7-methoxy-4-oxo-2-quinolonecarboxylic
acid, methyl ester from a substrate that was derived from O-methoxyaniline
afforded only 30% of one major cyclized product with several unidentified
side products (LC/MS studies).
Despite the generality described above, this methodology does
have certain limitations. In particular, the cyclization protocol
(20) Sauter, F.; Jordis, U.; Tanyolac, S. Sci. Pharm. 1988, 56, 73-80.
(21) Barker, J. M.; Huddleston, P. R.; Jones, A. W.; Edwards, M. J.
Chem. Res. 1980, 1, 4-5.
(23) Guy, A.; Guette, J-P.; Gerard, L. Synthesis 1980, 222-223.
4278 J. Org. Chem., Vol. 72, No. 11, 2007

Hz, 1H), 5.25 (s, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 3.67 (s, 3H). 13
C
Mechanistic studies for PPA-promoted cyclizations to ben-
zoxazole derivatives have been reported.24 While the report
discusses the similarity between the active species in Eaton’s
reagent and PPA, no mechanistic studies have been reported
for the cyclization of aniline derivatives to quinolones. As such,
it is currently unclear why the mixture of P2O5 and MeSO3H
serves to dramatically increase the rate of reaction. At the
simplest level, the mechanism of the cyclization reaction is likely
analogous to a Friedel-Crafts electrophilic aromatic substitution
reaction. Consistent with this, preliminary kinetic studies reveal
that electron rich substituents are more reactive than their
electron poor counterparts.25 Attempts to identify reaction
intermediates are currently underway.
In conclusion, we have developed a very mild, efficient and
scalable protocol for the synthesis of 4-quinolones, and qui-
nolone heterocycles using an inexpensive commercially avail-
able reagent. Future work will look at extending the conditions
employed in this study to the formation of thiochromenes and
other heterocycles.
NMR (125 MHz, DMSO-d6): δ ppm 169.0, 163.8, 149.9, 147.7,
128.4, 124.5, 120.6, 119.6, 111.5, 91.1, 55.5, 52.8, 51.1. m/z:
265.0950 [M+]. ESI-HRMS: calcd for C13H15NO5 266.1028 [M
+ H]+, found 266.1034.
Synthesis of 1,4-Dihydro-8-methoxy-4-oxo-2-quinolonecar-
boxylic Acid, Methyl Ester 1b. Enamine diester 1a (1.8 g, 6.6
mmol) was added to a round-bottom flask that was equipped with
a thermocouple and a stirrer, and Eaton’s reagent (7 mL) was then
added to the flask. The reaction mixture was aged at 50 °C, and
the progress of the reaction was followed by HPLC. HPLC
conditions: Zorbax RX-C8 column, 150 × 3 mm, gradient method,
ACN: 0.1% H3PO4 15:85 over 20 min hold 5 min at 80:20 then to
15:85 over 1 min. Flow rate ) 1 mL/min, λ ) 210 nm. Retention
time, 1a ) 18.0 min, 1b ) 12.2 min. When conversion reached
g98%, the reaction mixture was cooled to 5 °C and slowly
transferred to an excess saturated sodium carbonate solution that
was cooled to 10 °C. The solid was filtered, washed with 20 mL
of water, and dried in a vacuum oven at 50 °C. Compound 1b was
isolated as a white solid in 97% yield. This reaction has been scaled
as described in this procedure to multiple kilograms and gave 98%
isolated yield of 1b. 1H NMR (400 MHz, D3CCO2D): δ ppm 7.86
(d, J ) 8.2 Hz, 1H), 7.38 (t, J ) 8.2 Hz, 1H), 7.25 (d, J ) 8.2 Hz,
1H), 7.19 (s, 1H), 4.07 (s, 3H), 4.06 (s, 3H). 13C NMR (100 MHz,
D3CCO2D): δ ppm 181.3, 163.5, 149.7, 137.9, 131.6, 127.1, 126.3,
117.7, 112.9, 111.4, 57.1, 54.6. m/z: 233.0688 [M+]. ESI-HRMS:
calcd for C12H11NO4 256.0586 [M + Na]+, found 256.0586
Experimental Section
Synthesis of 2-Butenedioic Acid, 2-[(2-Methoxyphenyl)-
amino]-, Dimethyl Ester 1a. To a solution of o-anisidine (1 g,
8.1 mmol) in MeOH (10 mL) at 5 °C was added dimethyl
acetylenedicarboxylate (DMAD) (1.4 g, 9.7 mmol, 1.2 equiv). The
mixture was aged at rt over 2 h. The product precipitated during
the aging process. The yellow solid was filtered and washed with
MTBE (10 mL) followed by heptane (20 mL). Enamine diester 1a
Acknowledgment. We are grateful to Dr. Dave Tellers for
valuable suggestions, Dr. Tom Novak for HRMS analysis, Mr.
Richard Desmond for experimental assistance, and Dr. George
Zhou for FTIR studies.
1
was isolated as a yellow solid in 93% yield (2 g, 7.5 mmol). H
NMR (500 MHz, DMSO-d6): δ ppm 9.66 (s, 1H), 7.06 (m, 1H),
7.03(dd, J ) 8.2, 1.8 Hz, 1H), 6.88 (m, 1H), 6.79 (d, J ) 8.2, 1.8
Supporting Information Available: NMR spectra and ESI-
HRMS data for compunds (1-26). This material is available free
of charge via the Internet at http://pubs.acs.org.
(24) So, Y-H.; Heeschen, J. P. J. Org. Chem. 1997, 62, 3552-3561.
(25) Conversion of substrate with p-OMe substituent (Table 2, entry 11),
reached 40% over 40 min, while conversion of a substrate with p-NO2
substituent was only 3% over the same period.
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J. Org. Chem, Vol. 72, No. 11, 2007 4279