Construction of a quinoline ring via a 3-component reaction in water: Crystal structure analysis and H-bonding patterns of a 2-aryl quinoline

Article abstract of DOI:10.1039/c2gc35256g

Montmorillonite K-10 mediated green and one-pot synthesis of 2-substituted quinolines has been accomplished via a 3-component reaction of aniline, aldehydes and ethyl 3,3-diethoxypropionate in the presence of air oxygen in water. The crystal structure analysis and H-bonding patterns of one compound prepared are presented. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc35256g

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Construction of quinoline ring via a 3-component reaction in water:
crystal structure analysis and H-bonding patterns of a 2-aryl quinoline
T. Ram Reddy,a,b L. Srinivasula Reddy,a,b G. Rajeshwar Reddy,a Kaviraj Yarbagi,a Y. Lingappa,b D.
Rambabu,c,e G. Rama Krishna,d C. Malla Reddy,d K. Shiva Kumar,e Manojit Pale,*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
reaction of aniline (1), aldehydes (2) and ethyl 3,3-
diethoxypropionate (3) in the presence of montmorillonite K-
10 as a green and reusable catalyst and air oxygen in water
(Scheme 1). In view of the known antimicrobial activities of
55 quinolines1 we expected that the present class of compounds
would show relevant pharmacological properties.
Montmorillonite K-10 mediated green and one-pot synthesis
of 2-substituted quinolines has been accomplished via a 3-
component reaction of aniline, aldehydes and ethyl 3,3-
10 diethoxypropionate in the presence of air oxygen in water.
The crystal structure analysis and H-bonding patterns of one
compound prepared is presented.
EtO2C
R
N
Development of efficient and environmental friendly synthetic
methodologies for the commonly used small organic
15 molecules is one of the major challenges in modern organic
synthesis. Quinolines, because of their numerous
pharmacological properties are often considered as widely
used N-heterocycls in both academia and pharmaceutical
industries.1,2 It is not surprising that a number of methods
20 have been developed for the construction of quinoline ring
including Skraup, Doebner-Miller, Doebner, Combes or
Pfitzinger syntheses.2 Though very effective, many of these
methods however, often involve the use of various acids or
reagents that are not environmentally compatible, produce a
25 large amount of waste and require longer reaction times. The
multicomponent domino reactions are known to afford
structurally complex and diversity based molecules in a single
step operation that ensures high atom economy as well as
good overall yields.3 We envisioned that a similar strategy for
30 the construction of functionalized quinoline ring would not
only be beneficial for the development of a simpler and
straightforward method4 but also might increase the chances
of achieving a greener synthetic route. In continuation of our
interest in quinoline derivatives5 of potential pharmacological
35 interest we now wish to report a one-pot synthesis of 2-
substituted quinoline-3-carboxylate esters6 via 3-component
NH2
RCHO (2)
EtO2C
Montmorillonite-K10
H2O, 90 oC, air
OEt
+
EtO
OMe
OMe
MeO
OMe
3
4
1
Scheme 1. Green synthesis of quinolines via a MCR
In our initial study, the reaction of aniline 1a, 3,4-diflouro
60 benzaldehyde (2a) and ester 3 was carried out in water in the
presence of p-toluenesulfonic acid (p-TSA) and air at 90 ºC
when the corresponding quinoline 4a was isolated in 41%
yield (entries 1, Table 1). The use of other Lewis acids such
as ZnCl2, TiCl4 and SnCl4 was examined but was found to be
65 less effective as the expected product 4a was isolated in 10-
30% yield (entries 2-4, Table 1). We then examined the use of
montmorillonite K-10 (entry 5, Table 1). To our satisfaction,
the reaction proceeded well affording the desired product in
83% yield within 5h. To test the recyclability of the catalyst,
70 Montmorillonite-K10 was recovered by simple filtration and
reused when 4a was isolated without significant loss of its
yield. The yield of 4a was found to be 80, 77 and 75 after 1st,
2nd and 3rd recovery and resue of the catalyst. The use of
lower quantity of montmorillonite K-10 decreased the product
75 yield (entry 6 and 7, Table 1) whereas the reaction did not
proceed in the absence of catalyst indicating the key role
played by the catalyst (entry 8, Table 1). While water was
used as a solvent in all these cases, other solvents such as
EtOH (entry 9, Table 1), DMSO, DMF, acetonitrile, and
80 toluene however was found to be less effective in the present
MCR. Thus, a combination of Montmorillonite-K10 in water
was found to be optimal for the preparation of 4a.
--------------------------------------------------------------------------
aCustom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Bollaram Road Miyapur, Hyderabad 500 049, India.
40 bDepartment of Chemistry, Sri Venkateswara University, Tirupati 517
502, Andhra Pradesh, India.
cDepartment of Chemistry, K. L. University, Vaddeswaram, Guntur 522
502, Andhra Pradesh, India.
dDepartment of Chemical Sciences, Indian Institute of Science Education
45 and Research, Kolkata, West Bengal, 741252, India.
eInstitute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad, 500046, India. E-mail: manojitpal@rediffmail.com
†Electronic Supplementary Information (ESI) available: Experimental
Procedures, spectral data and copies of NMR for all new compounds.
50 CCDC 864149. For ESI See DOI: 10.1039/b000000x/
To test the generality and scope of this green MCR a range of
aldehydes (2) were employed under the optimized reaction
85 conditions7a (Table 2). Various electron donating e.g. F, Cl,
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Table 1. Effect of reaction conditions on the MCR of 1, 2a and 3.a
45 provided the desired product.9 The role of air oxygen was
further confirmed by the isolation of ethyl 2-(3,4-
difluorophenyl)-6,7-dimethoxy-1,2-dihydroquinoline-3-
carboxylate when the MCR of 1, 2a and 3 was carried out
strictly under inert atmosphere maintaining the other
50 conditions same as presented in entry 5 of Table 1.
CHO
MeO
MeO
CO2Et
Catalyst
1 +
+ 3
F
F
Solvent
heat, air
N
F
F
2a
4a
Table 2. Synthesis of 2-substituted quinolines (4)a (Scheme 1)
Entry
Catalyst
Solvent
%Yieldb,c
Entry
2; R =
Time (h) Products (4) % yieldb
1.
2.
3.
4.
5.
6.
7.
8.
9.
p-TSA (2.5 mol%)
ZnCl2(2.5 mol%)
TiCl4 (2.5 mol%)
SnCl4 (2.5 mol%)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
41
15
30
10
83 (80)d
41
28
0
35
1
2
3
2a; 3,4-diFC6H3
2b; 4-FC6H4
2c; 4-ClC6H4
5
6
7
4a
4b
4c
83
82
74
Montmorillonite-K10 (50% w/w)
Montmorillonite-K10 (20% w/w)
Montmorillonite-K10 (0.5% w/w)
No catalyst
4
5
2d; 2-BrC6H4
2e; 4-BrC6H4
5
5
4d
4e
75
81
Montmorillonite-K10 (50% w/w)
aAll the reactions were carried out using 1 (0.98 mmol), 2a (1.07 mmol)
and 3 (2.45 mmol) in a solvent at 90 °C for 5 h in the presence of air.
bWith respect to the aniline
Montmorillonite-K10 was used.
6
7
2f; 3,4-diMeC6H3
2g; 4-MeOC6H4
7
4f
82
75
5
1
used. cIsolated yield. dRecovered
10
4g
Br, Me and OMe (entries 1-7, Table 2) or electron
withdrawing groups e.g. NO2 and CF3 (entries 8 and 10, Table
2) present on the aryl ring of aldehydes were well tolerated.
8
9
2h; 4-NO2C6H4
2i; Ph
5
9
4h
4i
87
78
10 The reaction proceeded well irrespective of the substituents
present in aldehydes employed (entry 9 vs 1-7, 8 & 10, Table
2). The use of heteroaromatic and aliphatic aldehydes were
also successful and afforded the desired quinolines in good
yields (entries 11-13, Table 2). We then examined the use of
15 other aniline in place of 1. Thus, benzo[d][1,3]dioxol-5-amine
(5) was reacted with 3 and aldehyde 2a or 2h smoothly to give
the desired product 6a or 6b in good yield (Scheme 2). The
use of 1,1-diethoxyethane in place of 3 was also examined via
the reaction of 1 along with 2i when the desired product7b was
20 isolated in 70% yield. While all the new compounds
synthesized were well characterized by spectral (NMR, IR and
10
2j; 4-CF3C6H4
4j
89
5
6
8
6
11
12
13
2k; thiophen-2-yl
2l; furan-2-yl
2m; Me
4k
4l
81
71
62
4m
aAll the reactions were carried out using aniline 1 (0.98 mmol), aldehyde
(1.07 mmol), ethyl 3,3-diethoxypropionate (2.45 mmol) and
Montmorillonite K-10 (75 mg) in water at 90 °C in the presence of air.
55 bIsolated yields.
2
3
NH2
2a
2h
or
CO2Et
R
MS) data the molecular structure of
a representative
EtO2C
O
O
Montmorillonite-K10
compound 4j was established unambiguously by single crystal
X-ray diffraction (Fig. 1).8 The compound 4j crystalizes in the
25 monoclinic P21/c space group with one molecule in the
asymmetric unit (Z=0, Z’ = 2) (Figure 2). While the molecule
in the asymmetric unit as such had no conventional functional
groups to form H-bonding the ethyl ester and trifluoro groups
present however were responsible for the formation of weak
30 inter molecular H-bonding. The inversion related molecule in
the asymmentric unit forming the dimer synthon through C-
HꢀꢀꢀO interactions is shown in Fig. 2. They formed channels
with above one molecule and below one molecule via C-HꢀꢀꢀF
interactions and are stabilised by aromatic C-Hꢀꢀꢀπ
35 interactions. These interactions propagated in 3D network
packing along ac axis as shown in Fig. 3.
+
H2O, 90 oC, air
5-6h
N
EtO
OEt
O
O
6a; R= 3,4-diFC6H3 (82%)
6b; R = 4-NO2C6H4 (87%)
3
5
Scheme 2. Synthesis of quinolines 6a-b
Mechanistically, the reaction seems to proceed (Scheme 3) via
in situ generation of (i) an imine from the aniline (1) and
aldehyde (2) and (ii) a 3-hydroxy acrylate from ethyl 3,3-
40 diethoxypropanoate (3) under mild acidic conditions
employed. The Mannich reaction between the imine and 3-
hydroxy acrylate derivative followed by intramolecular
cyclization afforded the 1,2-dihydroquinoline intermediate
which on subsequent oxidation in the presence of air oxygen
60
Fig. 1.ORTEP representation of compound 4j (Thermal ellipsoids are
drawn at 50% probability level).
2
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research and technological advances” A. Méndez-Vilas (Ed.)
Vol 1, pp 72-83, ISBN (13): 978-84-939843-2-8, Formatex
Research Center, Badajoz, Spain, December 2011.
30
2. (a) V. V. Kouznetsov, L. Y. V. Méndez and C. M. M. Gómez,
Curr. Org. Chem. 2005, 9, 141 and references therein. (b) S.
Madapa, Z. Tusi and S. Batra, Curr. Org. Chem. 2008, 12,
1116 and references cited therein.
35
40
45
50
55
60
65
70
75
80
85
90
95
3. (a) A. D. Omling, I. Ugi, Angew. Chem. Int. Ed., 2000, 39,
3168; (b) J. Zhu and H. Bienaymé, Multicomponent Reactions,
Wiley-VCH, Verleg, Weinheim, 2005; (c) K. C. Nicolaou, D.
J. Edmonds, P. G. Bulger, Angew. Chem. Int. Ed., 2006, 45,
7134.
Fig. 2. The hydrogen bonding pattern in the molecule 4j.
4. For earlier synthesis of quinolines via MCR using a metal
catalyst in an organic solvent, see: (a) S. Sueki, C. Okamoto, I.
Shimizu, K. Seto and Y. Furukawa, Bull. Chem. Soc. Jpn.
2010, 83, 385; (b) T. Nakajima, T. Inada and I. Shimizu,
Heterocycles 2006, 69, 497.
5. (a) S. Pal, S. Durgadas, S. B. Nallapati, K. Mukkanti, R.
Kapavarapu, C. Lakshmi, K. V. L. Parsa and M. Pal, Bioorg.
Med. Chem. Lett. 2011, 21, 6573; (b) N. Mulakayala, D.
Rambabu, M. R. Raja, Chaitanya M., C. S. Kumar, A. M.
Kalle, G. R. Krishna, C. M. Reddy, M. V. B. Rao and M. Pal,
Bioorg. Med. Chem. 2012, 20,759; (c) M. Pal, I. Khanna, S.
Venkataraman, P. Srinivas and P. Sivram, World Patent
Application WO 2006058201, June 1, 2006.
6. For selected synthesis, see: (a) M. Balasubramanian, J. G.
Keay, In Comprehensive Heterocyclic Chemistry II; A. R
Katritzky, C. W. Rees, E. F. V. Scriven, Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, pp 245; (b) J. P. Michael, Nat. Prod.
Rep. 1997, 14, 605; (c) K. Kobayashi, R. Nakahashi, A.
Shimizu, T. Kitamura, O. Morikawa, H. Konishi, J. Chem.
Soc., Perkin Trans. 1999, 1, 1547; (d) C. Mitsos, A. Zografos,
O. Igglessi-Markopoulou, Chem. Pharm. Bull. 2000, 48, 211;
(i) J. N. Kim, H. J. Lee, K. Y. Lee, H. S. Kim, Tetrahedron
Lett. 2001, 42, 3737; (i) S. Sakaguchi, A. Shibamoto, Y. Ishii,
Chem. Commun. 2002, 180.
Fig. 3. The molecular arrangement along ac axis in molecule 4j.
3
OH
O
CO2Et
CO2Et
-H2O
R
CO2Et
R
H
MeO
N
H
N
H
MeO
N
R
air
4
1 + 2
5
Scheme 3. Proposed reaction mechanism
7. (a) General procedure for the synthesis of quinoline 4: A
mixture of Montmorillonite K-10 (75 mg), an appropriate
aniline 1 (0.98 mmol), ethyl 3,3-diethoxypropionate 3 (466
mg, 2.45 mmol) and an aldehyde 2 (1.07 mmol) in pure water
(7.5 mL, 5 times vol w. r. t. aniline) was stirred at 90 °C for
the time mentioned in Table 2 in the presence of air. After
completion of the reaction (indicated by TLC), the mixture
was cooled to room temperature and filtered. The filtrate was
extracted with EtOAc (3 x 5 mL). The organic layers were
collected, combined, dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using ethyl
acetate-hexane to give the desired product. (b) K. V. Rao, J.
Heterocyclic Chem. 1975, 12, 725.
To demonstrate the further scope of this MCR, structure
elaboration of quinoline 4a was carried out via the reaction
with morpholine (7) in the presence of 1,2,4-triazole to give
10 the corresponding amide
8 (Scheme 2). Some of the
quinolines (4) synthesized were teseted for their inhibitory
properties against Mycobacterium tuberculosis H37Rv
chorismate mutase (CM) in vitro.10 Compound 4a and 4b
showed 30% inhibition of CM when tested at 50 µM.
O
O
MeO
MeO
N
O
1,2,4-Triazole, DBU
8. Crystallographic data (excluding structure factors) for 4j have
been deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC 864149
(see also ESI).
4a
F
N
H
N
90 °C, 24 h
75%
F
7
8
15
9. The air oxygen has been reported to act as an effective oxidant
for aromatization of hydroquinolines, see: S.-Y. Tanaka, M.
Yasuda, A. Baba, J. Org. Chem., 2006, 71, 800.
Scheme 2. Structure elaboration of quinoline 4a.
In conclusion, a direct and one-pot synthesis of 2-substituted
quinolines of potential medicinal interest has been
accomplished via a 3-component reaction in water in the
10. While CM is considered as a promising target for the
identification of new antibacterial agents only a few small
molecules8 are known as inhibitors of CM, see: (a) A.Nakhi,
20 presence of air oxygen. Montmorillonite K-10 was identified
as green and reusable catalyst in this MCR. The
B. Prasad, R. M. Rao, U. Reddy, S. Sandra, R. Kapavarapu, D.
Rambabu, G. R. Krishna, C. M. Reddy, R. Kishore, P. Misra,
J. Iqbal and M. Pal, Med Chem Commun. 2011, 2, 1006; (b)
K. S. Kumar, R. Adepu, S. Sandra, D. Rambabu, G. R.
Krishna, C. M. Reddy, P. Misra, M. Pal, Bioorg. Med. Chem.
Lett. 2012, 22,1146; (c) K. S. Kumar, D. Rambabu, S. Sandra,
R. Kapavarapu, G. R. Krishna, M. V. B. Rao, K. Chatti, C. M.
Reddy, P. Misra and M. Pal, Bioorg. Med. Chem. 2012, 20,
1711.
a
methodology could be useful in constructing a diversity based
library of small molecules related to quinoline framework.
TRR thanks Dr V. Dahanukar and analytical group of DRL.
25 Notes and references
1. See for example: R. Musiol, T. Magdziarz and A. Kurczyk in
“Science against microbial pathogens: communicating current
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Graphical Abstract
Open to air
H2O
Montmorillonite-K10
NH2
R
N
EtO2C
OMe
OMe
+
RCHO
+
OEt
MeO
OMe
CO2Et
EtO
We describe green synthesis of 2-substituted quinolines via a 3-component reaction in water
along with the crystal structure analysis of a 2-arylquinoline.