A one-step synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid esters from o -nitrobenzaldehydes

Article abstract of DOI:10.1021/jo100392x

A straightforward and efficient one-step procedure for the synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl esters is described. The simple reductive cyclization is carried out by treating various substituted o-nitrobenzaldehydes with inex

Full text of DOI:10.1021/jo100392x

pubs.acs.org/joc
SCHEME 1. Synthesis of Quinoline-3-carboxylic Acid Ester
A One-Step Synthesis of 2,4-Unsubstituted
Quinoline-3-carboxylic Acid Esters from
o-Nitrobenzaldehydes
with the Gould-Jacobs Route
Hariharan Venkatesan,* Frances M. Hocutt,
Todd K. Jones, and Michael H. Rabinowitz
Johnson & Johnson Pharmaceutical Research and
Development L.L.C., 3210 Merryfield Row, San Diego,
California 92121
hvenkate@its.jnj.com
SCHEME 2. Transition Metal-Catalyzed Synthesis of
Quinoline-3-carboxylic Acid Ester
Received March 2, 2010
A straightforward and efficient one-step procedure for
the synthesis of 2,4-unsubstituted quinoline-3-carboxylic
acid ethyl esters is described. The simple reductive cycliza-
tion is carried out by treating various substituted o-nitro-
benzaldehydes with inexpensive, commercially available
times, elevated temperatures (and in one instance high
pressure), and expensive reagents, resulting in unsatisfactorily
low overall yields.5
Typically, substituted anilines can be converted to 4-hydroxy-
quinoline-3-carboxylate via the classical Gould-Jacobs reac-
tion. A two-step deoxygenation procedure then furnishes the
desired quinoline-3-carboxylate via conversion to the chloride
followed by reduction of the chloride under catalytic hydro-
genation conditions (Scheme 1).5c The route suffers from poorly
controlled regioselectivities in the first step and requires elevated
temperatures in the second step (250 °C). Furthermore, catalytic
hydrogenation can lead to over-reduction of the quinoline ring
and is incompatible with certain substituents such as the
chloride or the bromide, which are versatile handles for further
elaboration.
Recently, Nicholas and co-workers have reported a redu-
ctive cyclization of o-nitro-substituted Baylis-Hillman acet-
ates by CO, catalyzed by [Cp*Fe(CO)2]2 (Scheme 2).5d The
key step in this three-step route requires heating to high
temperature and pressure (150 °C at 6 atm of CO).
The routes described above require high temperatures
and/or pressures, are lengthy, and result in low overall yields
in most cases. This prompted us to investigate a more
practical and efficient route. In our search for a simpler pro-
cedure for the synthesis of quinoline-3-carboxylates, we felt
that we could use the well-known Friedlander synthesis to
our advantage.4,6 Several groups have investigated variations
3,3-diethoxypropionic acid ethyl ester and SnCl2 2H2O in
refluxing ethanol.
3
The quinoline ring system is a prevalent structural motif in
natural products1 as well as in numerous marketed drugs
such as antibacterials, antimalarial agents, HIV-1 integrase
inhibitors,2 and other compounds of pharmaceutical inter-
est.3 As part of our ongoing drug discovery efforts, we
required a rapid, efficient, and practical synthesis of sub-
stituted quinoline-3-carboxylic acids. Despite the existence
of extensive literature for the synthesis of quinolines,4 the
routes available to specifically synthesize 2,4-unsubstituted
3-carbalkoxy quinolines were, to our surprise, limited. Most
common procedures require multiple steps, long reaction
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166–187. (b) Jones, G. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 5, pp 167-245.
(2) (a) Wagman, A. S.; Wentland, M. P. In Comprehensive Medicinal
Chemistry II; Taylor, J. B., Triggle, D. J., Eds.; Elsevier Ltd: Oxford, UK,
2006; Vol. 7, pp 567-596. (b) Charris, J. E.; Dominguez, J. N.; Gamboa, N.;
Rodrigues, J. R.; Angel, J. E. Eur. J. Med. Chem. 2005, 40, 875–881. (c) Dayam,
R.; Al-Mawsawi, L. Q.; Zawahir, Z.; Witvrouw, M.; Debyser, Z.; Neamati, N.
J. Med. Chem. 2008, 51, 1136–1144.
(3) (a) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia, M. Eur.
J. Med. Chem. 2000, 35, 1021–1035. (b) Maguire, M. P.; Sheets, K. R.;
McVety, K.; Spada, A. P.; Zilberstein, A. J. Med. Chem. 1994, 37, 2129–
2137.
(4) (a) Larsen, R. D.; Cai, D. Sci. Synth. 2005, 15, 389–549. (b) Fan, J.;
Wan, C.; Sun, G.; Wang, Z. J. Org. Chem. 2008, 73, 8608–8611. (c)
(5) (a) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Kim, H. S. Tetrahedron Lett.
2001, 42, 3737–3740. (b) Kim, J. N.; Chung, Y. M.; Im, Y. J. Tetrahedron
Lett. 2002, 43, 6209–6211. (c) Ohnmacht, C. J.; Davis, F.; Lutz, R. E. J. Med.
Chem. 1971, 14, 17–24. (d) O’Dell, D. K.; Nicholas, K. M. J. Org. Chem.
2003, 68, 6427–6430.
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M. D. C.; Soriano, E. Chem. Rev. 2009, 109, 2652–2671. (b) Cheng, C.-C.;
Yan, S.-J. Org React. 1982, 28, 37–200.
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3488 J. Org. Chem. 2010, 75, 3488–3491
Published on Web 04/26/2010
DOI: 10.1021/jo100392x
r
2010 American Chemical Society

Venkatesan et al.
JOCNote
SCHEME 3. Proposed Synthesis of Quinoline-3-carboxylic
Acid Ester
TABLE 1. Synthesis of 6-Chloroquinoline-3-carboxylic Acid Methyl
Ester from 2-Amino-5-chlorobenzaldehyde
of the reaction using acidic as well as basic conditions.7
However, to the best of our knowledge, only one synthesis
of 2,4-unsubstituted quinoline-3-carboxylic acid utilizing the
Friedlander reaction starting from a substituted 2-amino-
benzaldehyde has been disclosed and is of limited practical
value due to the low overall yield (13%).8 Moreover, the
aldehyde partner that is required to affect this transforma-
tion, 3-oxo-propionic acid ethyl ester, is not readily available
commercially, although it can be synthesized in a single step.9
In contrast, the corresponding ethyl acetal is both inexpen-
sive and commercially available. This synthon shares the
parent aldehyde’s reactivity profile under the Friedlander
conditions and we elected to investigate this reagent in the
Friedlander reaction. Herein, we report a rapid, modified
Friedlander synthesis of aryl-substituted quinoline-3-carbo-
xylic acid esters from commercially available ethyl 3,3-di-
ethoxypropionate and o-nitrobenzaldehydes (Scheme 3).
At first, we elected to test the viability of the cyclization
reaction using 2-amino-5-chlorobenzaldehyde under a vari-
ety of acidic conditions (Table 1). We were pleased to find
that treatment of 5-chloro-2-aminobenzaldehyde with 3,3-
dimethoxy methyl propionate in the presence of 4 M HCl in
dioxane at room temperature yielded the desired product,
albeit in low yield (entry 1). Heating the reaction mixture to
reflux did not improve the yield of the reaction (entry 2).
However, heating the reaction mixture with AcOH resulted
in good yield of the product (entry 3). Acids such as TFA,
MsOH, and CSA led to considerable decomposition and
moderate yields of product (entries 4, 5, and 6). The use of
PPTS in THF led to moderate yields of the desired product
(entry 7). We found that, performing the reaction in toluene
or THF using p-TsOH under refluxing conditions provided
the best yields of 6-chloroethyl quinoline-3-carboxylate
(67% and 76% respectively, entries 9 and 10). We have per-
formed the optimized procedure on a number of other amino
benzaldehydes that were not commercially available (data
not shown) and have consistently obtained good yields of the
quinoline-3-carboxylates (>70% typically).
entry
1
solvent
dioxane 4 M HCl
(anhydrous)
dioxane 4 M HCl
(anhydrous)
acid
temp (°C) time (h) yield (%)
rt
21
30
2
100
21
32
3
4
5
6
7
8
9
10
AcOH
TFA
THF
THF
THF
100
100
80
80
80
110
110
80
23
22
19
19
19
17
17
17
60
41
50
40
44
63
67
76
MeSO3H
CSA
PPTS
dioxane p-TsOH
toluene
THF
p-TsOH
p-TsOH
Two reagents that have been used extensively for the
reduction of the nitro group are Na2S2O4 and Fe/acid.10
First, we attempted to perform the one-pot procedure using
o-nitrobenzaldehyde, alkyl 3,3-dialkoxypropionate (methyl
or ethyl), and Na2S2O4 in refluxing acetic acid and obtained a
low yield of the desired product (21% and 20% respectively,
entries 1 and 2, Table 2). Additionally, we found that the
reaction under these conditions was capricious and irrepro-
ducible. The use of Na2S2O4 and TsOH in toluene did not
yield any of the desired product (entry 3). Similarly, the use
of iron and HCl or iron and p-TsOH in EtOH and toluene,
respectively, did not yield any product (entries 4 and 5). The
nitro group underwent reduction smoothly under these
reaction conditions but failed to cyclize.
SnCl2 can function as a chemoselective reducing agent11 as
well as a mild Lewis acid and was therefore an attractive
reagent for carrying out this reductive cyclization. Using
SnCl2 2H2O in refluxing EtOH we consistently obtained
3
good yields of the desired product (entry 6, 82% average over
2 runs). The reaction was further optimized by varying the
time and the number of equivalents of SnCl2 2H2O required
3
for the transformation. We found that 4 equiv of SnCl2
3
2H2O were necessary to give optimal yields of product.
Depending on the substrate, the reaction time generally
varied between 1.5 and 4 h. The reaction is operationally
very simple: all reagents are mixed in EtOH and refluxed
until the reaction is complete, prior to aqueous workup and
isolation by flash column chromatography.
Having established the optimal conditions for the reac-
tion, we then examined a variety of substituted o-nitrobenz-
aldehydes to explore the scope and limitations of the reaction
(Table 3).
Encouraged by the results, we wished to extend the utility
of the reaction and explore the possibility of affecting a one-
step reductive cyclization of o-nitrobenzaldehydes. Success
in this more complex transformation would allow access to a
much greater number of commercially available aromatic
aldehyde starting materials.
The reaction accommodates a range of functional groups,
including electron-withdrawing as well as electron-releasing
substituents on the nitrobenzaldehyde. Also, under these
reaction conditions, it is worth noting that bromides, chlori-
des, ester, and methoxy groups as well as the O-benzyl group
are tolerated (entries 2-5 and 7-10). Amine substitutions
(7) (a) Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, P. J.
Org. Lett. 2001, 3, 1101–1103. (b) Yasuda, N.; Hsiao, Y.; Jensen, M. S.;
Rivera, N. R.; Yang, C.; Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer,
P. G.; Volante, R. P.; Hughes, D. L.; Reider, P. J. J. Org. Chem. 2004, 69,
1959–1966. (c) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257–
4259. (d) Li, A.-H.; Ahmed, E.; Chen, X.; Cox, M.; Crew, A. P.; Dong, H.-Q.;
Jin, M.; Ma, L.; Panicker, B.; Siu, K. W.; Steinig, A. G.; Stolz, K. M.;
Tavares, P. A. R.; Volk, B.; Weng, Q.; Werner, D.; Mulvihill, M. J. Org.
Biomol. Chem. 2007, 5, 61–64.
(8) Tom, N. J.; Whritenour, D. C. U.S. Pat. Appl. US2002042516A1,
2002.
(9) Haupt, A.; Unger, L.; Drescher, K.; Jongen-Relo, A. L.; Grandel, R.;
Braje, W.; Geneste, H. PCT Int. Appl. WO2006015842A1, 2006.
(10) (a) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem.
€ €
1985, 50, 5782–5789. (b) Raitio, K. H.; Savinainen, J. R.; Vepsalainen, J.;
€
Laitinen, J. T.; Poso, A.; Jarvinen, T.; Nevalainen, T. J. Med. Chem. 2006, 49,
2022–2027.
(11) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839–842.
J. Org. Chem. Vol. 75, No. 10, 2010 3489

Venkatesan et al.
JOCNote
TABLE 2. Optimization of Reductive Cyclization
entry
R
acid
reducing agent
solvent
time/temp
yield (%)
1
2
3
4
5
6
Me
Et
Me
Et
Me
Et
AcOH
AcOH
TsOH
HCl
TsOH
SnCl2
Na2S2O4
Na2S2O4
Na2S2O4
Fe
Fe
SnCl2
AcOH
AcOH
toluene
EtOH
toluene
EtOH
3 h at 65 °C and 3 h at 110 °C
3 h at 65 °C and 3 h at 100 °C
3 h at 65 °C and 18 h at 110 °C
18 h at 95 °C
21
20
0
0
0
82
18 h at 100 °C
3 h at 90 °C
TABLE 3. Scope of One-Step Modified Friedlander Reaction
SCHEME 4. 3-Ethoxy Ethyl Acrylate Mediated Synthesis of
Quinoline-3-carboxylic Acid Ethyl Ester
such as pyrrolidine, piperidine, and dimethylamine provide
more modest yields relative to other substrates (entries 13,
14, and 16). It seemed reasonable to hypothesize that the
reaction proceeds through the intermediacy of 3-alkoxy
acrylate and we tested this hypothesis by performing the
reaction using commercially available 3-ethoxy ethyl acry-
late (Scheme 4). The use of this reagent in the reductive
Friedlander reaction provided yields of desired product
comparable to those observed from ethyl 3,3-diethoxypro-
pionate (67% for 5-chloro-2-nitrobenzaldehyde and 73% for
4-trifluoromethyl-2-nitrobenzaldehyde).
In summary we have developed a simple procedure for the
synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid
esters from o-nitrobenzaldehydes in good yield using an
inexpensive, commercially available synthon. The efficient
methodology described here represents the shortest route
available to access a variety of 2,4-unsubstituted 3-carboxy-
quinolines, tolerates a range of functional groups, is oper-
ationally simple, and provides a significant improvement
over existing routes for the preparation of this class of
molecules.
Experimental Section
General Procedure for Acid-Catalyzed Cyclization: 6-Chloro-
quinoline-3-carboxylic Acid Ethyl Ester (Table 1, entry 9). 3,3-
Dimethoxypropionic acid methyl ester (0.71 mL, 5.0 mmol) was
added to a solution of 5-chloro-2-aminobenzaldehyde (0.311 g,
2.00 mmol) and toluene (5 mL), followed by p-TsOH (38 mg,
0.20 mmol). The reaction mixture was heated to 110 °C for 18 h.
Saturated aqueous NaHCO3 was then added and the mixture
was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated. The
residue was purified by flash chromatography (SiO2, 0-25%
EtOAc/hexanes) to yield a pale yellow crystalline solid (0.264 g,
67%): mp 168.6-169.5 °C (lit. mp 174-176 °C); 1H NMR (600
MHz, CDCl3) δ 9.43 (d, J=2.1 Hz, 1H), 8.75 (d, J=1.9 Hz, 1H),
8.10 (d, J=9.0 Hz, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.76 (dd, J=9.0,
2.3 Hz, 1H), 4.03 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 165.5,
150.2, 148.2, 137.7, 133.3, 132.7, 131.1, 127.6, 127.5, 123.8, 52.7.
Anal. Calcd for C11H8ClNO2: C, 59.61; H, 3.64; N, 6.32. Found:
C, 59.70; H, 4.00; N, 6.35.
a3,3-dimethoxy methyl propionate in refluxing methanol was
used.
3490 J. Org. Chem. Vol. 75, No. 10, 2010

Venkatesan et al.
JOCNote
General Procedure for Tin(II) Chloride-Mediated Reductive
Cyclization: Quinoline-3-carboxylic Acid Ethyl Ester (Table 2,
entry 6). Tin(II) chloride dihydrate (1.81 g, 8.00 mmol) was
added to a solution of 2-nitrobenzaldehyde (0.302 g, 2.00 mmol)
and EtOH (10 mL) followed by 3,3-diethoxypropionic acid ethyl
ester (0.97 mL, 5.0 mmol). The reaction mixture was heated to
90 °C for 4 h. Upon cooling, the reaction mixture was concen-
trated and the residue was dissolved in EtOAc and quenched
with saturated aq NaHCO3. The resulting emulsion was filtered
through a pad of Celite, and rinsed well with EtOAc. The remai-
ning aqueous layer was extracted with EtOAc and the combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The residue was purified by flash chromatogra-
phy (SiO2, 10-30% EtOAc/hexanes) to yield an off-white solid
(0.331 g, 82%): mp 67.4-67.9 °C (lit. mp 69-69.5 °C); 1H NMR
(600 MHz, CDCl3) δ 9.46 (d, J=2.1 Hz, 1H), 8.85 (d, J=1.7 Hz,
1H), 8.17 (d, J=8.5 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.84 (ddd,
J=8.4, 6.9, 1.4 Hz, 1H), 7.66-7.60 (m, 1H), 4.49 (q, J=7.1 Hz,
2H), 1.47 (t, J=7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ
165.4, 150.1, 149.8, 138.7, 131.8, 129.5, 129.1, 127.4, 126.9,
123.3, 61.5, 14.4. Anal. Calcd for C12H11NO2: C, 71.63; H,
5.51; N, 6.96. Found: C, 71.31; H, 5.66; N, 6.72.
Acknowledgment. We warmly thank Victor Phuong and
Alice Lee-Dutra for kindly providing 4-bromo-2-nitrobenzal-
dehyde and 2-nitro-5-phenoxybenzaldehyde, respectively.
Supporting Information Available: 1H and 13C NMR,
melting points, and copies of spectra for all prepared com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 10, 2010 3491