One-Pot Synthesis of Highly Substituted Quinolines in Aqueous Medium and Its Application for the Synthesis of Azalignans

Article abstract of DOI:10.1002/ejoc.202000906

A new one-pot method has been developed for the synthesis of highly substituted quinoline derivatives from α-amino ketone derivatives/glycine esters/glycine amide and aromatic/aliphatic alkynes/alkenyl esters using molecular I₂, K₂CO₃, and tetra butyl ammonium bromide (TBAB) and sodium dodecyl sulfate (SDS) surfactant combination in water at room temperature within 30–50 min. in moderate to good yields. This protocol has advantages like oxidant free, aqueous medium, simple operation, tolerance of various substrates, and useful for the synthesis of bioactive aza-lignans.

Full text of DOI:10.1002/ejoc.202000906

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: One pot Synthesis of Highly Substituted Quinolines in Aqueous
Medium and its Application for the Synthesis of Azalignans
Authors: Amrendra Kumar, Rmanand Prajapati, Ruchir Kant, and
Tadigoppula Narender
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000906
Link to VoR: https://doi.org/10.1002/ejoc.202000906
01/2020

10.1002/ejoc.202000906
European Journal of Organic Chemistry
MUNICATION
One pot Synthesis of Highly Substituted Quinolines in Aqueous
Medium and its Application for the Synthesis of Azalignans
Amrendra Kumar,[a] Ramanand Prajapati,[a] Ruchir Kant[b] and Narender Tadigoppula*[a]
Abstract: A new one-pot method has been developed for the
sulphate (SDS) surfactant combination in water at room
temperature within 30-50 min. in moderate to good yields. This
protocol has advantages like oxidant free, aqueous medium, simple
operation, tolerance of various substrates and useful for the
synthesis of bioactive aza-lignans.
synthesis of highly substituted quinoline derivatives from α-amino
ketone
derivatives/glycine
esters/glycine
amide
and
aromatic/aliphatic alkynes/alkenyl esters using molecular I2, K2CO3
and tetra butyl ammonium bromide (TBAB) and sodium dodecyl
Introduction
Quinoline subunits are widespread in natural products[1] and
key structures of several pharmaceutical compounds[2]
(Figure 1). These moieties have been reported to possess a
diverse range of biological properties such as anti-
inflammatory,[2b]
anticancer,[3]
antimicrobial,[4]
and
antipsychotics.[5] Mancheno and co-workers, in 2011, have
synthesized various substituted quinolines from glycine
derivatives using FeCl3 by oxidative dehydrogenative
coupling/aromatization tandem reaction for the first time
(Scheme 1a).[6] In 2014, Huo and co-workers synthesized
quinolines in presence of air as the oxidant by using an auto-
oxidation coupling system and CBr4.[7] Recently Liu and co-
workers developed the Cu(II)-catalyzed aerobic oxidative C-H
functionalization of glycine derivatives with olefins using N-
hydroxy phthalimide (NHPI) as a co-catalyst and O2 as the
oxidant.[8] In all of the above transformations the iminium
intermediates were generated by oxidation and subsequently
captured by olefins and some of the reactions were carried
out at high temperature, used toxic solvents, metal catalysts
and additives, which are harmful for the environment and
human health. Selective protocols for the synthesis of highly
substituted quinoline derivatives with minimum number of
steps and the reduced toxic waste materials are in great
demand. In this direction very recently Yang and co-workers
Figure 1. Bioactive molecules containing quinoline structures.
developed
a
direct photocatalytic aerobic oxidative
dehydrogenative coupling-aromatization tandem reaction for
the synthesis of substituted quinolines from glycine esters
and unactivated alkenes under mild reaction conditions
(Scheme 1b).[9]
Scheme 1. Existing methods for the synthesis of highly substituted
quinolines.
In continuation of our methodology development work, we
discovered a new protocol for the synthesis of highly
substituted quinolines from α-amino ketones and alkynes in
the presence of molecular I2 using K2CO3 as a base and
surfactants tetrabutyl ammonium bromide (TBAB) and sodium
dodecyl sulphate (SDS) combination and very mild reaction
condition comparatively previous reports (Scheme 1c).
[a]
Mr. Amrendra Kumar, Mr. Ramanand Prajapati, and
Prof. Dr. T. Narender
Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute,
Lucknow-226031, India
E-mail: t_narendra@cdri.res.in
https://www.cdri.res.in/1551.aspx?id=1551
Dr. Ruchir Kant
[b]
Molecular and Structural Biology Division,
CSIR-Central Drug Research Institute,
Lucknow-226031, India.
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/ejoc.202000906
European Journal of Organic Chemistry
MUNICATION
Table 1. Optimization of the reaction conditions between 1-(4-chloro
phenyl)-2-((4-methoxy phenyl)amino)ethan-1-one (α-amino ketone) (1a)
and 1-ethynyl-3-methoxy benzene (2a).
Reaction conditions. α-Amino ketone 1a (1 equiv.), Alkyne 2a (0.7 equiv.),
I2 (2.0 equiv.) in 1.5 ml of water at room temperature. NR = No reaction; a
equivalents: bIsolated yields; c1 equivalent of I2
2
OMe
We initiated the test reaction between 1-(4-chlorophenyl)-2-
(4-methoxyphenyl)amino ketone 1a and alkyne 2a as model
substrates to explore the reaction conditions using anionic
surfactant SDS (Table 1). To our delight, the desired product
3aa was obtained in 20% yield within 65 min using (2 equiv.)
of iodine, (2 equiv.) of K2CO3 in combination with (10 mol %)
SDS as a surfactant in water at room temperature (Table 1,
entry 1). The chemical structure of 3aa has been confirmed
by spectral data and single crystal X-ray crystal data (CCDS
No. 1845131). The low yield of the product 3aa was attributed
to insufficient quantity of surfactant in aqueous medium.
Increasing the SDS loading from 10 to 30% mole was helpful
to further improve the yield of the desired product 3aa to 56%
with reduced reaction time from 65 min to 42 min (Table 1,
entry 2-3).The cationic surfactants such as tetra butyl
ammonium iodide (TABI) and tetra butyl ammonium bromide
(TBAB) (Table-1, entries 4-5) and non-ionic surfactants such
as triton X-100, tween 80 and pluronic F-127 (Table 1, entries
6-8) were screened, however, none of them were efficient.
We then moved on to test the various surfactants
combination to improve the reaction conditions. Pleasingly,
the SDS (40%) and TBAB (40%) combination was the most
effective (Table 1, entry 11), affording 3aa in 89% yield after
30 min at room temperature. Other combinations such as
SDS (40 mole %) and TBAI (40 mole %), SDS (40%) and
tritonx-100 (40 mole %), SDS (40 mole %) and tween-80 (40
mole %), SDS (40 mole %) and pluronic F-127 (40 mole %)
gave 3aa in yield of 71%, 64%, 63% and 73% respectively
(Table 1, entries 12-15). Decreasing the quantity of iodine
from 2 equiv. to 1 equiv. and base K2CO3 2 equiv. to 1 equiv.
gave low yield of 3aa (Table 1, entry 16). Reaction with iodine
agents such as KI, NIS (N-iodo succinamide) and ICl failed to
provide the desired quinolines (Table 1, entries 17-19). We
also investigated the same reaction in the presence of few
organic polar solvents at room temperature, however,
relatively low yields were observed, when compared with
aqueous conditions (Table 1, entries 22-25). Cs2CO3 is as
good as K2CO3, however NaHCO3 failed to give desired
product may be due to weak basicity (Table 1, entries 20-21).
In the absence of surfactants, the reaction did not give
product in the aqueous medium (Table 1, entry 26).
MeO
Cl
MeO
Cl
N
N
OMe
H
O
O
2a
3aa
1a
Entry
Basea
Surfactant
(mole%)
Solvent
Time
(min)
Yieldb
(%)
1
2
3
4
5
6
I2/K2CO3
I2/K2CO3
I2/K2CO3
I2/K2CO3
I2/K2CO3
I2/K2CO3
SDS (10)
SDS (20)
SDS (30)
TBAB (40)
TBAI (40)
Water
Water
Water
Water
Water
Water
65
55
20
45
56
51
46
NR
42
44
53
Tritonx-100
(40)
120
7
8
I2/K2CO3
I2/K2CO3
Tween 80 (40)
Water
Water
140
53
NR
50
Pluronic
F-127 (40)
9
I2/K2CO3
I2/K2CO3
I2/K2CO3
I2/K2CO3
I2/K2CO3
SDS (30) +
TBAB (20)
Water
Water
Water
Water
Water
42
37
30
35
43
71
75
89
71
64
10
11
12
13
SDS (30) +
TBAB (30)
SDS (40) +
TBAB (40)
SDS (40) +
TBAI (40)
SDS (40) +
Tritonx-100
(40)
14
15
I2/K2CO3
I2/K2CO3
SDS (40) +
Water
Water
41
23
63
73
Tween 80 (40)
SDS (40) +
Pluronic F-127
(40)
16c
17
18
19
20
21
I2/K2CO3
KI/K2CO3
NIS/K2CO3
ICl/K2CO3
I2/Cs2CO3
I2/NaHCO3
SDS (40) +
TBAB (40)
Water
Water
Water
Water
Water
Water
DMF
60
60
60
60
28
60
55
NR
NR
NR
83
SDS (40) +
TBAB (40)
SDS (40) +
TBAB (40)
With optimized conditions in our hand, we explored the
substrate scope of our protocol in order to show the
generality of the reaction (Table 2). A variety of substituted α-
amino ketones 1a-1l were investigated with substituted aryl
alkynes 2a-2l and synthesized respective quinolines 3aa-3kg
with the yield ranging from 42 to 89%. The compounds, which
have electron donating-groups on the phenyl group (ring-A)
of α-amino ketone gave good yields in comparison to electron
withdrawing groups, which is evident from the yields of 3ac
(76%), 3cc (66%) and 3ec (59%). On the other hand electron
withdrawing groups on ring B of α-amino ketone improves the
yields of the products 3ac (76%), 3bc (71%) and 3dc (68%).
Substitution pattern on phenyl group (ring-C) of alkyne also
influence on the yields of product. The electron withdrawing
groups such as fluoro and bromo on phenyl (ring-C) of alkyne
SDS (40) +
TBAB (40)
SDS (40) +
TBAB (40)
SDS (40) +
TBAB (40)
NR
22
23
I2/K2CO3
I2/K2CO3
None
None
105
90
59
45
1,4
Dioxane
24
25
26
I2/K2CO3
I2/K2CO3
I2/K2CO3
None
None
None
DMSO
Toluene
Water
120
70
26
38
130
NR
2
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10.1002/ejoc.202000906
European Journal of Organic Chemistry
MUNICATION
however the yield was poor (Scheme 2), when compared with
glycine esters 1l-1n.
gave low yields. For example, the compound 3bc, which has
bromo substitution on para position of phenyl ring of alkyne
gave 71% of yield, where as its fluoro substituted compound
gave 61%. Similarly, the bromo substituted compound 3cc
was isolated in 66% of yields, where as fluoro substituted
compound 3cf was isolated in 49% only. Electron releasing
groups at para position of phenyl group of alkyne improves
the yields. This trend can be observed when we compare the
yields of 3bg (73%) vs 3bf (61%) and 3ch (81%) vs 3cf
(49%). It is also noteworthy to mention here that reaction with
aliphatic alkyne also led to respective quinoline derivative 3ad.
R2
I2 2 equiv
K2CO3 2 equiv
R1
R1
R
R2
R
N
H
SDS, (40mol %)
TBAB (40mol %)
H2O, rt, 30-50 min.
N
O
O
3ld-3om
1l-1o
2d-2m
Me
Me
Me
F
MeO
MeO
MeO
MeO
O
N
O
O
O
N
N
O
N
O
O
Table 2. Substrate scope of the α-amino ketones 1a-1k and substituted
phenyl acetylenes 2a-2l and isolated yields of substituted quinolines.
O
3ll (49%)
3lf (49%)
3lg (49%)
3ld (57%)
F
H3
C
MeO
H3C
O
O
N
O
O
N
N
O
O
3mf (38%)
3mm (48%)
3lm (67%)
MeO
MeO
O
NH2
N
N
O
O
3om (39%)
3nm (69%)
Scheme 2. Substrate scope of glycine derivatives for the synthesis of
substituted quinolines
We then focused on to use activated phenyl alkynes, such as
ethyl (E)-3-phenyl acrylate 2n, ethyl (E)-3-(p-tolyl)acrylate 2o,
ethyl (E)-3-(4-fluoro phenyl)acrylate 2p instead of phenyl
alkynes. Delightedly, the reaction between α-amino ketone 1a
and 2n proceeded smoothly and furnished the highly
functionalized quinoline 3an with 77% yield (Scheme 3). With
this success, we further reacted 2n with ethyl (4-methoxy
phenyl)glycinate 1l, which also gave quinoline 3ln in 64%
yield. Interestingly, the quinoline derivative 3ln has two ester
functionalities adjacent to each other, which are useful
functionalities for converting them in to azalignan class of
compounds. We therefore reacted 1l with few more activated
alkynes such as 2n-2p and prepared respective quinolone
derivatives 3ln-3lp, which have di-ester functionality. Here
also, the alkynes, which have electron donating groups gave
better yields than electron withdrawing groups 3lo vs 3lp.
#- ORTEP diagram drawn with 30% ellipsoid probability for non-H atoms of
the crystal structure of compound 3aa determined at 293 K.
We next examined the glycine ester derivatives such as ethyl
(4-methoxy phenyl)glycinate 1l, ethyl p-tolyl glycinate 1m and
ethyl 4-methoxy phenyl glycinate 1n and substituted phenyl
alkynes 2d, 2f, 2g, 2l and 2m which have successfully
furnished the desired products 3ld-3om (Scheme 2). Glycine
esters which have stronger electron releasing groups on its
phenyl ring gave better yields (3lm 67% vs 3mm 48%; 3lf
49% vs 3mf 38%). In contrast, electron withdrawing nitro and
halo-substituted glycine esters failed to give the desired
quinoline derivatives. Phenyl acetylenes with electron
withdrawing groups furnished low yields of 3lf and 3mf. The
glycine amide derivative 2-(p-tolyl amino)acetamide (1o) also
successfully furnished the desired quinoline product 3om,
Scheme 3. Substrate scope of ethyl 3-phenyl propiolates for the synthesis
of highly substituted quinoline derivatives.
To demonstrate further application of this protocol for the
synthesis nitrogen containing lignan type of natural products,
we carried out a reductive cyclization reaction on quinolines
containing di-ester functionality such as 3ln-3p using LiAlH4
3
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10.1002/ejoc.202000906
European Journal of Organic Chemistry
MUNICATION
To understand the mechanism of reaction, few control
experiments were carried out as shown in (Scheme 7). None
of the control experiments without iodine produced desired
product 3ac (Scheme 7 c, d and f). However, in the absence
of 2c with standard reaction conditions iminium intermediate
17 was obtained from 1a (Scheme 7 b). We were fortunate to
isolate and characterize the iminium intermediate 17 (Scheme
7, b)/III (Scheme 8) and use it for onward reaction with 2c to
give highly substituted quinoline 3ac. It is also interesting to
report here that the molecular iodine alone can also produce
the desired product from α-amino ketones 1a and its imine
(III/17), however the yield was very poor (Scheme 7, e and g).
The base K2CO3 is playing a key role to increase the reaction
rate to improve the yields. The HI generated in the reaction
mixture might have reconverted into iodine by aerobic
oxidation in water.[11]
(1.2 equiv.) in dry THF at 0°C for 25 min to produce the
desired lignans 4a-4c in good yields (Scheme 4).[10]
Scheme 4. Synthesis of aza-lignans.
Next, we investigated a few hetero aromatic acetylenes
such as 2-ethynyl thiophene 5a and 3-ethynyl thiophene
7a (Scheme 5). Both compounds (5a and 7a) were
reacted with α-amino ketone 1a under optimised
conditions to affords the respective substituted quinolines
6aa (73%) and 8aa (79%). However, the reaction
between α-amino ketones 1a and nitrogen containing
hetero aromatic acetylene 2-ethynyl pyridine 9a did not
give the desired product 10aa under the standard
reaction conditions (Scheme 5).
Scheme 5. Synthesis of hetero aryl containing quinolines.
Further, the reaction between α-amino ketone 1a and
styrene 11a/1,2-diphenyl ethene 13a/1,2-diphenyl
acetylene 15a failed to produce the desired product
12aa/14aa/16aa under similar reaction conditions
(Scheme 6).
Scheme 7. Control experiments.
The possible reaction mechanism for the formation of highly
substituted quinolines appears to be in the presence of the
micellar system of SDS and TBAB the solubility of reactants
improved in water (Scheme 8). The proton abstraction by K2CO3
in 1a, might led to carbanion species I, which might have attacked
on I2 to give iodinated species II. Elimination of HI from II might
have led to generation of imine intermediate III. Phenyl alkyne 2c
might have reacted in the presence of Iodine with intermediate III
followed by inter molecular cyclization to give tetra hydro
quinoline species IV. To increase the stability, hydrogen ion might
have shifted as in V followed by aerobic oxidation to give highly
substituted quinoline derivative 3ac.
Scheme 6. Exploration of quinoline synthesis with styrene (11a)/1,2-
diphenyl ethene (13a)/ diphenyl acetylene (15a).
4
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10.1002/ejoc.202000906
European Journal of Organic Chemistry
MUNICATION
References
[1]
a) J. P. Michael, Nat. Prod. Rep. 2007, 24, 223-246; b) J. P.
Michael, Nat. Prod. Rep. 2008, 25, 166-187; c) J. P. Michael, Nat.
Prod. Rep. 1997, 14, 605-618; d) D. C. Behenna, J. L. Stockdill, B.
M. Stoltz, Angew. Chem. Int. Ed. 2008, 47, 2365-2386; e) L. K.
Kong, Y. Zhou, H. Huang, Y. Yang, Y. Li, Y. Z. J. Liu, J. Org.
Chem. 2015, 80, 1275-1278.
[2]
a) K. Andries, P. Verhasselt, J. Guillemont, Göhlmann, H. W. H.
Neefs, J.-M. Winkler, H. Van Gestel, J. Timmerman, P. Zhu, M. Lee,
E. Williams, P. de Chaffoy, D. Huitric, E. Hoffner, S. Cambau, E.
Truffot-Pernot, C. Lounis, N. Jarlier, Science 2005, 307, 223−237;
b) B. D. Bax, P. F. Chan. Eggleston, D. S. Fosberry, A. Gentry, D. R.
Gorrec, F. I. Giordano, M. M. Hann, A. Hennessy, M. Hibbs, J.
Huang, E. Jones, J. Jones, K. K.Brown, C. J. Lewis, May, E. W.
Saunders, M. R. Singh, O. Spitzfaden, C. E. Shen, C. Shillings, A.
Theobald, A. J. Wohlkonig, A. N. D.Pearson; M. N. Gwynn, Nature
2010, 466, 935−940; c) D. C. Behenna; J. L. Stockdil, B. M. Stoltz,
Angew. Chem. Int. Ed. 2008, 47, 2365−2383; d) N. Jeedimalla, M.
Flint, L. Smith, A. Haces, D. Minond, S. P. Roche, European
Journal of Medicinal Chemistry 2015, 106, 167-179.
Scheme 8. Possible reaction mechanism.
In conclusion, we have developed a new approach for the
synthesis of highly substituted quinolines, which involves the
C(sp3)-H
functionalization
of
amino-ketones/glycine
esters/glycine amide by molecular iodine followed by
elimination of HI to generate imine and attack of
aromatic/aliphatic, alkynes/alkenyl ester on imine and
subsequent aerobic oxidative aromatization in tandem using
K2CO3 and surfactants combination (SDS and TBAB) in water.
Our protocol is operationally simple and avoids use of any
oxidant, toxic metal or organic solvents. We have also
demonstrated broad scope of the reaction for the synthesis of
substituted quinolines and bioactive aza-lignans.
[3]
[4]
a) S. Vlahopoulos, E. Critseli, I. F. Voutsas, S. A. Perez, C. N.
Baxevanis, G. P. Chrousos, Curr. Drug Targets 2014, 15, 843−851;
b) V. R. Solomon; H. Lee, Curr. Med. Chem. 2011, 18, 1488−1508.
S. Kumar, S. Bawa, H. Gupta, Mini-Rev. Med. Chem. 2009, 9,
1648−1654.
[5] P. Zajdel, A. Partyka, K. Marciniec, A. J .Bojarski, M. Pawlowski, A.
Wesolowska, Future Med. Chem. 2014, 6, 57−75.
[6] a) H. Richter, O. G. Mancheño, Org. Lett. 2011, 13, 6066-6069; b)
Rohlmann, T. Stopka, H. Richter, O. G. Mancheño, J. Org. Chem.
2013, 78, 6050-6064; c) R. Morrison, T. Belz, S. K. Ihmaid, J. M. A.
Rawi, M. J. Angove, Med. Chem. Res. 2014, 23, 4680-4691.
General procedure for synthesis of poly substituted
quinolines
[7]
[8]
[9]
C. Huo, Y. Yuan, M. Wu, X. Jia, X. Wang; F. Chen; J. Tang, Angew.
Chem. Int. Ed. 2014, 53, 13544-13547.
Z. Y. Xie, J. Jia, X. G. Liu, L. Liu, Adv. Synth. Catal. 2016,
358, 919-925.
In an oven dried 50 ml R.B flask charged with stir bar, α-keto-
amine (0.02 g, 0.94 mmol, 1.0 equiv.), alkyne (0.067 g, 0.66
mmol, 0.7 equiv.), Iodine (0.720 g, 2.84 mmol, 2.0 equiv.),
K2CO3 (0.392 g, 2.84 mmol, 2.0 equiv.), sodium dodocyl
sulphate (SDS), (0.327 g, 0.37 mmol, 0.4 equiv), tetrabutyl
ammonium bromide (TBAB) (0.366 g, 0.37 mmol, 0.4 equiv)
and water (5.0 mL), resulting mixture was stirred at rt for 30-
50 min. After completion of reaction monitored by TLC (1:7
ethyl acetate and hexane) was cooled down to room
temperature and diluted with 10 mL of H2O. The resultant
mixture was extracted with ethyl acetate (3 × 15 mL). The
combined organic phase was dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, the
crude product was purified by column chromatography on
silica gel (100-200 mesh) by using hexane/ethylacetate
solvent system to give desired poly substituted quinoline
compounds.
X. Yang, L. Li, Y. Li, and Y. Zhang, J. Org. Chem. 2016, 81, 12433-
12442.
[10] Y. Hitotsuyanagi, M. Kobayashi, M. Fukuyo, K. Takeya, H. Itokawa,
Tetrahedron Letters 1997, 38, 8295-8296.
[11] E. Steinle, R. Charles R. Greene US patent.US2918354A.
Acknowledgements
We thank the Director, CSIR-CDRI, for financial support, the
SAIF Division for spectral data, Dr. Tejendar Thakur for X-ray
crystal data the CSIR, New Delhi, for fellowship to Amrendra.
This is CDRI Communication number 88/2018/NT
Keywords: α-Amino ketone • Phenyl acetylene • TBAB, SDS•
C(sp3)-H functionalization • Iodine • quinolines
5
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10.1002/ejoc.202000906
European Journal of Organic Chemistry
MUNICATION
A one-pot method has been developed for the synthesis of highly substituted quinoline derivatives through C(sp3)-H functionalization of α-
amino ketone derivatives/glycine esters/glycine amide by iodine, nucleophelic substitution by aromatic/aliphatic alkynes/alkenyl esters and
aerobic oxidative aromatization in tandem using K2CO3 and tetrabutyl ammonium bromide (TBAB) and sodium dodecyl sulphate (SDS)
surfactant combination in water at room temperature within 30-50 min. in moderate to good yields.
Key topic: C(sp3)-H functionalization
Institute twitter user name:@CSIR-CDRI
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