Synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl esters from arylmethyl azides via a domino process

Article abstract of DOI:10.1039/c3ob27493d

A convenient synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl esters via a domino process is described. The synthesis employs arylmethyl azides as the precursor which undergoes an acid-promoted rearrangement to give an N-aryl iminium ion. Following the addition with ethyl 3-ethoxyacrylate, intramolecular electrophilic aromatic substitution, elimination and subsequent oxidation, the quinoline products were obtained in moderate to excellent yields.

Full text of DOI:10.1039/c3ob27493d

Organic &
Biomolecular Chemistry
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COMMUNICATION
Synthesis of 2,4-unsubstituted quinoline-3-carboxylic
acid ethyl esters from arylmethyl azides via a domino
process†
Jumreang Tummatorn,*a Charnsak Thongsornkleeb,a,b Somsak Ruchirawata,b and
Tanita Gettongsonga
Cite this: Org. Biomol. Chem., 2013, 11,
1463
Received 23rd December 2012,
Accepted 16th January 2013
DOI: 10.1039/c3ob27493d
www.rsc.org/obc
A
convenient synthesis of 2,4-unsubstituted quinoline-
3-carboxylic acid ethyl esters via a domino process is described.
The synthesis employs arylmethyl azides as the precursor which
undergoes an acid-promoted rearrangement to give an N-aryl
iminium ion. Following the addition with ethyl 3-ethoxyacrylate,
intramolecular electrophilic aromatic substitution, elimination and
subsequent oxidation, the quinoline products were obtained in
moderate to excellent yields.
Fig. 1 Examples of pharmaceutical interest containing
a 2,4-unsubstituted
The quinoline ring system constitutes an important structural
scaffold in various natural products which reveal numerous
biologically significant properties such as antimicrobial,1 anti-
TB,2 anticancer,3 anti-HIV,4 and antimalarial activities.5 The
quinoline skeleton is often an attractive framework to be used
in the design of several synthetic compounds against diverse
pharmacological targets leading to discovery of new drugs.
Therefore, many methods for the synthesis of quinolines6 have
been developed including Combes quinoline synthesis,7
Conrad–Limpach synthesis,8 Friedlander synthesis,9 Camps
quinoline synthesis,7c Knorr quinoline synthesis,10 Skraup
synthesis,11 Niementowski quinoline synthesis,12 Povarov
reaction,13 Gould–Jacobs reaction,14 and Doebner–Miller
reaction.15
quinoline-3-carboxylate skeleton.
time, high temperature and expensive starting materials
(Scheme 1).17 To improve the preparation of these compounds
(3), factors such as commercial availability of substrates pos-
sessing wide structural variety as well as the ease of prep-
aration of these substrates, when they are not commercially
available, must be considered. These are important in evaluat-
ing the practicality and efficiency of these synthetic methods.
Recently, Venkatesan and co-workers have reported a con-
venient and efficient one-step procedure for the synthesis of
2,4-unsubstituted quinoline-3-carboxylic acid ethyl ester 3
from o-nitrobenzaldehydes (5) and 3,3-diethoxypropionic acid
ethyl ester (6) in the presence of SnCl2·2H2O under refluxing
In particular, 2,4-unsubstituted quinoline-3-carboxylate
derivatives have recently received much interest from pharma-
ceutical industries as this core structure is present in many
agents under development to become commercial drugs, some
of which are exemplified in Fig. 1.16
However, practical ways to synthesize this crucial core struc-
ture (3) are rare in the literature. The currently available
methods require a long multi-step synthesis, long reaction
aChulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210,
Thailand. E-mail: jumreang@cri.or.th; Fax: +66 2 574 0622;
Tel: +66 2 574 0622 ext 1513
bProgram on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence
on Environmental Health and Toxicology, CHE, Ministry of Education,
54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
†Electronic supplementary information (ESI)
available. See DOI:
Scheme 1 Synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl
ester 3.
10.1039/c3ob27493d
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Scheme 3 Synthesis of arylmethyl azide derivatives.
Scheme 2 Synthetic strategy for the synthesis of 2,4-unsubstituted quinoline-
3-carboxylic acid ethyl ester 3.
quinoline product improved from 67% to 79% (entry 5) when
the reaction time was decreased. From these results, we specu-
lated that the desired quinoline product may have been
decomposed under these strongly acidic conditions in pro-
longed reaction time. We also attempted the reaction in
toluene at 0 °C and observed a complex reaction mixture.
Additionally, we attempted the reaction in toluene and THF
using TiCl4 and obtained only starting material unreacted
(entries 7 and 8). The reaction in toluene in the presence of 2.0
equiv. of ethyl 3-ethoxyacrylate (2) and 1.0 equiv. of TfOH at
room temperature was chosen as the general method.
We then applied these optimal conditions to a variety of
arylmethyl azide substrates to verify the generality of the
method. Various arylmethyl azide substrates can be prepared
in two steps in good to excellent yields from the corresponding
arylmethyl alcohols 11 as shown in Scheme 3.21
conditions.17f However, this method does not allow for ade-
quate diversity and substitution on the quinoline ring system 3
due to the limited number of commercially available o-nitro-
benzaldehyde derivatives, some of which are expensive. More-
over, o-nitrobenzaldehyde derivatives are difficult to obtain by
most processes.18
Our research group has been investigating the azide
rearrangement reactions that deliver the N-aryl iminium ion
intermediate 1a′ which can be trapped with a variety of nucleo-
philes.19 Relating to this chemistry, we envision that 2,4-
unsubstituted quinoline-3-carboxylic acid ethyl ester 3 could
be generated by nucleophilic addition of ethyl 3-ethoxyacrylate
(2) to the iminium ion followed by intramolecular electrophilic
aromatic substitution and oxidation, constituting a domino
process,20 as shown in Scheme 2.
To search for the optimal conditions for our proposed qui-
noline synthesis, we used benzyl azide (1a) as our substrate for
optimization. Based on earlier work both by our group and
others,19 TfOH and TiCl4 are most optimal to effect the
rearrangement of arylmethyl azides in either dichloromethane
(DCM) or toluene. Therefore, we first investigated the
rearrangement–cyclization sequence using 1.0 equiv. of TfOH
and 1.0 equiv. of ethoxyacrylate 2 in DCM, which only provided
24% of the desired quinoline after oxidation with 1.0 equiv. of
DDQ (entry 1, Table 1). We then switched to toluene and
found that yield could be slightly improved to 38%. We next
increased the amount of the acrylate to 2.0 equiv. while
keeping everything else unchanged and found that yields in
both solvents improved significantly, although toluene was
still superior. Moreover, we found that the yield of the desired
As summarized in Table 2, the reactions proceeded readily
with o-tolylmethyl azide (1b) and 2,3-xylylmethyl azide (1c) to
give the desired quinolines 3b and 3c in 76% and 83% yields,
respectively. When the aromatic ring was substituted with an
electron-donating group (entry 4), the quinoline product 3d
was obtained in only 24% yield. The reaction of nitro-substi-
tuted benzyl azide 1e furnished the product 3e in lower yield
(14%). We also attempted the reaction with m-fluorobenzyl
azide (1f) and m-chlorobenzyl azide (1i) and obtained a
mixture of regioisomeric products in both cases; 10% and 28%
yields (entry 6), and 17% and 14% yields (entry 9), respectively.
Moreover, the effects of halobenzyl azide derivatives with
different substitution patterns were explored (entries 7–8 and
10–11). For o-chlorobenzyl azide (1g), the quinoline product
was obtained in 54% yield. For p-chlorobenzyl azide (1h), the
reaction provided a mixture of the quinoline product 3h and
the uncyclized by-product 16 (RvCl) which could not be separ-
1
ated. However based on H-NMR analysis of the purified pro-
Table 1 Optimization of the synthesis of 2,4-unsubstituted quinoline-3-car-
boxylic acid ethyl ester 3a
ducts, the yield of the quinoline product was determined to be
ca. 71% (Method A). Bromine substitution was also tolerated
in this reaction (1j and 1k). For p-bromobenzyl azide (1k),
upon purification the reaction also provided an inseparable
mixture of the quinoline 3k and the uncyclized by-product 16
(RvBr); the yield of 3k was determined to be ca. 78% based on
1H-NMR analysis (Method A). Substrates with more complexity
also provided the desired quinoline products in moderate to
good yields (entries 12–16). However, when the secondary aryl-
methyl azide 1q was employed (entry 17), only a trace amount
of the desired 2-methyl quinoline product 3q was observed by
1H-NMR in the complex reaction mixture.
Entry
Acids
Solvent
Equiv. (2)
Time (h)
Yielda (%)
1
2
3
4
5
6b
7
8
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TiCl4
TiCl4
CH2Cl2
Toluene
CH2Cl2
Toluene
Toluene
Toluene
Toluene
THF
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
12
12
12
12
3
3
12
12
24
38
57
67
79
40
NR
NR
The reaction mechanism of this process is proposed as
illustrated in Scheme 4. An acid-promoted rearrangement of
arylmethyl azide for the generation of an N-aryl iminium ion
serves as a key step. The iminium ion formed reacted with 2 to
a Isolated total yield over 2 steps. b The reaction was carried out at 0 °C
to room temperature.
1464 | Org. Biomol. Chem., 2013, 11, 1463–1467
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Table 2 Optimization of the synthesis of 2,4-unsubstituted-3-carbalkoxy quinolines 3
Entry
1
Substrate
Product
Yielda (%)
79
Entry
10
Substrate
Product
Yielda (%)
70
2
3
4
76
11
12
13
14
53b
56c
55c
83
77
55c
59c
24
14
53
70
5
6
7
54
15
56
8
9
36b
56c
16
17
64
Trace
a Method A: (1) benzylic azide (1.0 equiv.), TfOH (1.0 equiv.), toluene, rt, 3 h, then 2 (2.0 equiv.); (2) DDQ (1.0 equiv.), EtOAc, rt, 5 min. b The reaction was carried out according to Method A,
except after 2 h at rt the reaction was heated to 90 °C for 1 h. c Method B: (1) benzylic azide (1.1 equiv.), TfOH (1.1 equiv.), toluene, rt, then BF3·OEt2 (1.0 equiv.), then 2 (1.0 equiv.).

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Acknowledgements
This research work was supported in part by grants from
Center of Excellence on Environmental Health and Toxicology,
Science and Technology Postgraduate Education and Research
Development Office (PERDO), Ministry of Education, Chulab-
horn Research Institute, and Thailand Research Fund
(TRG558008). We thank Mr Nitirat Chimnoi for his kind assist-
ance in the mass spectrometric analyses.
Scheme 4 Proposed reaction mechanism.
generate the oxonium ion intermediate 12. This intermediate
can either undergo intramolecular electrophilic aromatic sub-
stitution and elimination of ethanol to afford the presumably
dihydroquinoline intermediate 13 which was not isolable22
and was directly oxidized with DDQ to yield the desired quino-
line product 3 (path a) or undergo elimination to obtain ethoxy-
acrylate 15 (RvBr) which could be isolated. Upon oxidation of
15 (RvBr) with DDQ, uncyclized by-product 16 (RvBr) was
obtained (path b).
The results showed that the competition between the for-
mation of the desired quinoline product 3 (path a) and un-
cyclized by-products 16 (path b) depended on the reactivity of
the aromatic ring. To suppress the formation of these by-pro-
ducts, we tried to heat the reaction mixture to 90 °C; while the
by-products were not observed after heating, unfortunately the
yields of the desired quinolines (3h and 3k) dropped to 36%
and 53%, respectively. We speculated that the ethoxyacrylate 2
could act as a proton acceptor which may cause path b to be
more favorable when the aromatic ring was not reactive
enough to cyclize. Therefore, we decided to make compound 2
the limiting agent and used 1.1 equiv. of benzylic azide
(entries 8 and 11). We then tried several Lewis acids to
promote the cyclization step and found that BF3·OEt2
(Method B)23 could increase the yields of 3h and 3k to 56% in
both cases (compared to 36% and 53%, see above) and no
uncyclized by-products were observed. However, this method
provided the quinoline products in lower yields compared to
Method A. We also applied Method B to benzylic azides in
entries 2, 3, 6, 9 and 12. Yields of the desired quinoline pro-
ducts were moderate, however, yields of products in entries 6
and 9 were significantly higher compared to Method A.
Notes and references
1 (a) S. Sabatini, F. Gosetto, G. Manfroni, O. Tabarrini,
G. W. Kaatz, D. Patel and V. Cecchetti, J. Med. Chem., 2011,
54, 5722–5736; (b) R. Nandhakumar, T. Suresh,
A. L. C. Jude, V. R. Kannan and P. S. Mohan, Eur. J. Med.
Chem., 2007, 42, 1128–1136; (c) A. H. Kategaonkar,
P. V. Shinde, A. H. Kategaonhar, S. K. Pasale, B. B. Shingate
and M. S. Shingare, Eur. J. Med. Chem., 2010, 45,
3142–3146.
2 A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S. G. Franzblau
and A. P. Kozikowski, J. Med. Chem., 2009, 52, 2109–2118.
3 Y.-W. Chen, Y.-L. Chen, C.-H. Tseng, C.-C. Liang,
C.-N. Yang, Y.-C. Yao, P.-J. Lu and C.-C. Tzeng, J. Med.
Chem., 2011, 54, 4446–4461.
4 J. P. Michael, Nat. Prod. Rep., 2008, 25, 166–187.
5 (a) F. Bellot, F. Coslédéric, L. Vendier, J. Brocard,
B. Meunier and A. Robert, J. Med. Chem., 2010, 53,
4103–4109; (b) R. Klingenstein, P. Melnyk, S. R. Leliveld,
A. Ryckebusch and C. Korth, J. Med. Chem., 2006, 49,
5300–5308; (c) V. K. Zishiri, M. C. Joshi, R. Hunter,
K. Chibale, P. J. Smith, R. L. Summers, R. E. Martin and
T. J. Egan, J. Med. Chem., 2011, 54, 6959–6968.
6 P. E. Alford, in Progress in Heterocyclic Chemistry, ed.
G. W. Gribble and J. A. Joule, Elsevier, Ltd., Oxford, 2011,
vol. 23, pp. 349–358.
7 (a) E. C. Franklin and F. W. Bergstrom, Chem. Rev., 1944,
35, 77–277; (b) J. L. Born, J. Org. Chem., 1972, 37,
3952–3953; (c) R. H. Manske, Chem. Rev., 1942, 30,
113–144.
8 (a) R. H. Reitsema, Chem. Rev., 1948, 43, 43–68;
(b) G. A. Reynolds and C. R. Hauser, in Organic Syntheses,
ed. C. S. Hamilton, John Wiley & Sons, 1949, vol. 29, p. 70.
9 (a) P. G. Dormer, K. K. Eng, R. N. Farr, G. H. Humphrey,
J. C. McWilliams, P. J. Reider, J. W. Sager and R. P. Volante,
J. Org. Chem., 2003, 68, 467–477; (b) S. S. Palimkar,
S. A. Siddiqui, T. Daniel, R. J. Lahoti and K. V. Srinivasan,
J. Org. Chem., 2003, 68, 9371–9378; (c) R. Martínez,
D. J. Ramón and M. Yus, J. Org. Chem., 2008, 73,
9778–9780.
Conclusions
In conclusion, we have developed a new method for the syn-
thesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl
esters 3 via a domino process starting from arylmethyl azide
derivatives 1 and ethyl 3-ethoxyacrylate (2) in two synthetic
steps and requiring only one purification. The current syn- 10 (a) C. R. Hauser and G. A. Reynolds, J. Am. Chem. Soc.,
thetic method can be conveniently conducted on a wide
variety of the azide substrates. In addition, BF3·OEt2 could be
1948, 70, 2402–2404; (b) A. J. Jodgkinson and B. Staskun,
J. Org. Chem., 1969, 34, 1709–1713.
used to promote the same process which required less amount 11 (a) R. H. F. Manske and M. Kulka, Org. React., 1953, 7,
of acrylate 2.
59–98; (b) H. T. Clarke and A. W. Davis, in Organic
1466 | Org. Biomol. Chem., 2013, 11, 1463–1467
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Synthesis, ed. J. B. Conant, John Wiley & Sons, 1922, vol. 2,
p. 79.
12 R. J. Chongau, M. A. Siddiqui and V. Snieckus, Tetrahedron
Lett., 1986, 27, 5323–5326.
J. Org. Chem., 2003, 68, 6427–6430; (e) R. E. Lutz,
C. J. Ohnmacht, Jr. and F. Davis, J. Med. Chem., 1971, 14,
17–24; (f) H. Venkatesan, F. M. Hocutt, T. K. Jones and
M. H. Rabinowitz, J. Org. Chem., 2010, 75, 3488–3491.
13 (a) H. Twin and R. A. Batey, Org. Lett., 2004, 6, 4913–4916; 18 (a) C. I. Sainz-Diaz and A. Hernandez-Laguna, J. Chem.
(b) H. Richter and O. G. Mancheño, Org. Lett., 2011, 13,
6066–6069; (c) M. J. Bouma, G. Masson and J. Zhu,
Eur. J. Org. Chem., 2012, 475–479.
Soc., Perkin Trans. 2, 1999, 1489–1495; (b) C. I. Sainz-Diaz,
Monatsh. Chem., 2002, 133, 9–22; (c) W. Ertel, US Patent US
4297519, 1991; (d) W. Meyer, US Patent US 4203928, 1980.
14 R. G. Gould and W. A. Jacobs, J. Am. Chem. Soc., 1939, 61, 19 (a) J. Tummatorn, C. Thongsornkleeb and S. Ruchirawat,
2890–2895.
Tetrahedron, 2012, 68, 4732–4739; (b) W. H. Pearson and
W.-K. Fang, Isr. J. Chem., 1997, 37–39; (c) P. Desai,
K. Schildknegt, K. A. Agrios, C. Mossman, G. L. Milligan
and J. Aubé, J. Am. Chem. Soc., 2000, 122, 7226–7232;
(d) Z. Song, Y.-M. Zhao and H. Zhai, Org. Lett., 2011, 13,
6331–6333.
15 (a) M. Matsugi, F. Tabusa and J.-I. Minamikawa, Tetra-
hedron Lett., 2000, 41, 8523–8525; (b) J. J. Eisch and
T. Dluzniewski, J. Org. Chem., 1989, 54, 1269–1276.
16 (a) P. Weikop, M. B. Nielsen, L. S. Madsen and
C. Mathisen, Patent WO 2008/31831 A2, 2008; (b) J. Mitchell
and H. Fields, Patent US 2006/258647 A1, 2006; 20 L. F. Tietze, G. Brasche and K. M. Gericke, Domino Reactions
(c) A. Phadke, D. Chen, M. Meshpande, A. Thurkauf,
in Organic Synthesis, Wiley VCH, Weinheim, Germany,
X. Wang, Y. Shen, C. Liu, J. Quinn, J. Ohkanda and S. Li,
2006.
Patent US 2006/25416 A1, 2006; (d) J. D. Bloom, 21 Safety precaution should be taken seriously when prepar-
K. J. Curran, M. J. Digrand, R. G. Dushin, S. A. Lang,
E. B. Norton, A. A. Ross and B. M. O’Hara, Patent EP
1137645 B1, 2004.
ing benzylic azides. Dichloromethane from the first step
should be removed completely to avoid the formation of
diazidomethane when using NaN3 in the next step. See:
R. E. Conrow and W. D. Dean, Org. Process Res. Dev., 2008,
12, 1285–1286.
17 (a) J. N. Kim, H. J. Lee, K. Y. Lee and H. S. Kim, Tetrahedron
Lett., 2001, 42, 3737–3740; (b) J. N. Kim, Y. M. Chung and
Y. J. Im, Tetrahedron Lett., 2002, 43, 6209–6211; 22 We attempted to isolate this intermediate, however the
(c) H. J. Kim, E. M. Jeong and K.-J. Lee, J. Heterocycl. Chem., intermediate decomposed on silica gel during purification.
2011, 48, 965–972; (d) D. K. O’Dell and K. M. Nicholas, 23 See ESI† for optimization of Method B.
This journal is © The Royal Society of Chemistry 2013
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