The: P -toluenesulfonic acid catalyzed single pot synthesis of tetracyclic 1,2-dihydroquinolines: A metal free approach

Article abstract of DOI:10.1039/c6nj00928j

A simple, convenient and efficient p-toluenesulfonic acid catalyzed tandem reaction of aliphatic ketones with substituted anilines towards the synthesis of polysubstituted 1,2-dihydroquinolines has been developed. The ready availability of the catalyst, operational simplicity, cost effectiveness of the process and excellent regioselectivity mark some of the highlights of this methodology.

Full text of DOI:10.1039/c6nj00928j

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DOI: 10.1039/C6NJ00928J
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ARTICLE
p-Toluenesulfonic acid catalyzed single pot synthesis of tetracyclic
1,2-Dihydroquinolines: a metal free approach
Anil K. Hajare,a Arun R. Jagdale,a G. Gautham Shenoyb and Neelima Sinhaa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple, convenient and efficient p-Toluenesulfonic acid catalyzed metathesis. However, most of the literature methods suffer
from drawbacks in terms of poor yields, low regioselectivity,
and use of expensive organometallic complexes. Furthermore,
many methodologies involve complex multistep pathways,
harmful solvents and drastic conditions, thus limiting their
utility towards scalable synthesis. In this context, there exists
enough scope to come up with a versatile and efficient
methodology involving milder reaction conditions towards an
easy access to this important family of compounds.
In the recent decade, p-toluene sulphonic acid (p-TSA) has
emerged as a useful eco-friendly acid catalyst which has been
effectively employed in the development of wide variety of synthetic
methodologies. In our continued interest towards synthesis of
substituted indoles, we envisioned to employ p-TSA as a catalyst.
Towards meeting our goal, we attempted condensation of aniline (1)
with cyclopentanone (2) in the presence of p-TSA to form
imine/enamine 3a-b as a key precursor for the synthesis of tricyclic
dihydroquinoline 4 (scheme 1).
tandem reaction of aliphatic ketones with substituted anilines
towards the synthesis of polysubstituted 1,2-dihydroquinolines has
been developed. Ready availability of catalyst, operational
simplicity, cost effective process and excellent regioselectivity
marks some of the highlights of this methodology.
1,2-Dihydroquinolines and their derivatives are ubiquitous
skeletons found in a variety of natural products1 that have been
extensively used as important subunits to design biologically
active molecules of pharmaceutical interest. They have been
reported to possess excellent anti-bacterial, anti-diabetic, and
anti-inflammatory
activities.
Besides
exhibiting
pharmacological properties,2 dihydroquinolines are also being
employed in industrial purposes as antioxidants for the purpose
of preserving animal nutriments and vegetable oils. For
example
Ethoxyquin
(6-ethoxy-1,2-dihydro-2,2,4-
trimethylquinoline) , FDA approved agent3 which is widely used
in the food industry.
In light of being a privileged heterocyclic scaffold, over the
years, 1,2-dihydroquinolines have generated a lot of interest
towards their synthesis4. In the literature, Skraup et al. reported
initial quinoline synthesis by heating a mixture of nitroethane,
aniline, and glycerol in presence of concentrated sulfuric acid in
a low yield.5 Since then, there have been numerous methods
developed in the literature towards the synthesis of 1,2-
dihydroquinolines. Typically, reaction of aryl amines with
various class of organic compounds such as ketones,6 α,β-
unsaturated ketones,7 2,2-dimethoxy propane,8 aldehyde,9
alkynes,10 α- ketoester11 in the presence of iodine, Lewis acid or
Brønsted acid catalysts affords 1,2-dihydroquinolines. Other
reported methods starting from respective functionalized
anilines include transition-metal catalysts, or a cascade of
reactions viz. Michael/aldol12 or allylic amination/ring closing
Scheme 1 Synthesis of imine
To our surprise, the reaction underwent through an alternative
pathway to afford tetracyclic dihydroquinoline 5 in a single step,
instead of the intended imine/enamine 3a-b. It is apparent that two
molecules of ketone and aniline underwent sequential reaction to
furnish dihydroquinoline 5. Encouraged by this unpredicted finding,
we decided to explore further and widen the scope of this reaction
on diversely substituted anilines and other aliphatic ketones.
To start with our study; aniline was reacted with
cyclopentanone at 100°C using p-TSA as the catalyst affording
dihydroquinoline (5). Systematic study was then carried out
using different solvents like DMF, Toluene, Methanol, DMSO,
THF; various acid catalysts such as Acetic acid, TFA, Triflic acid,
p-TSA; and at variable temperature and time to optimise the
a.Novel Drug Discovery & Development, Lupin Limited, 1st Floor, Genesis Square
Building, Hinjewadi, Phase-2, Village - Man, Tal. Mulshi, Dist. - Pune,
Maharashtra, India, 411057.
b.Manipal College of Pharmaceutical Sciences, Manipal University, Manipal,
Karnataka, India, 576104.
† Electronic Supplementary Information (ESI) available: Experimental details, 1H
NMR and 13C spectra of all compounds. See DOI: 10.1039/x0xx00000x
reaction condition. We found that, reaction of aniline (1) with
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J. Name., 2013, 00, 1-3 | 1
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cyclopentanone (
2
) at 140°C, in presence of p-TSA in DMF as the dihydroquinolines (8a-l) by employing substitutedVaienwilAirntieclse Ownilitnhe
) in optimal yields (Table 1, various ketones. Diversely substituted anilines were treated
solvent afforded dihydroquinoline (
entry i). No reaction was observed in the absence of acid and with ketones (
both the starting materials were recovered unchanged (Table 1, afford the corresponding dihydroquinolines (8a-l and 10a-g) in
5
DOI: 10.1039/C6NJ00928J
7
and 9) under optimized reaction conditions to
entry k). The results are summarised in Table 1.
moderate to good yields (Table 2-3).
In particular, meta-substituted anilines exhibited excellent
regioselectivity with good yields (Table 2, entry 8e-h). Anilines
bearing electron donating substituents at meta position
(Cl˂Me˂NHAc≤OMe) afforded better yields as compared to
para-substituted anilines (entry 8b-d). In comparison, yields
were diminished in case of ortho-substituted anilines (entry 8i-
j), which could be attributed to steric effect of the ortho
substituent on the arylamine.
Table 1. Reaction optimizationa
NH2
O
cat. Acid
+
N
H
2
5
1
Entry Solvent
Temp Acid
(oC)
Yield
(%)b
Table 3: Reaction of anilines with acyclic ketonesa
a
b
c
d
e
f
g
h
i
Toluene
THF
MeOH
DMF
DMSO
DMF
DMF
DMF
DMF
DMSO
DMF
100
100
100
100
100
100
100
100
140
140
140
PTSA
PTSA
PTSA
PTSA
PTSA
0
13
18
20
18
5
Acetic acid
TFA
Triflic acid
Product Yield (%)b
10(a-c)
8
Entry Aniline R1
(6)
11
26
24
0
PTSA
PTSA
None
a
b
c
d
e
f
H
-CH3
10a
10b
10c
10d
10e
10f
10g
43
56
52
41
45
60
54
j
k
3-OMe -CH3
a Reaction condition: Aniline (5 mmol), cyclopentanone
(10 mmol), acid catalyst (20 mol%), DMF (5 mL), 20 h.
b Isolated yields
3-Me
3-Cl
H
-CH3
-CH3
-CH2CH3
3-OMe -CH2CH3
3-Me -CH2CH3
Table 2: Reaction of anilines with cyclic ketonesa
g
aReaction condition: aniline (5 mmol), ketone as a solvent
(10 mL), p-TSA (20 mol%), 20 h. b Isolated yields
The scope of the reaction was further extended by reacting
cyclohexanone (Table 2, entry 8k-l) and acyclic ketones 9 under
optimized reaction condition. It was observed that, increase in
the ring size from cyclopentanone (Table 2, n=1) to
cyclohexanone (Table 2, n=2) resulted in slight decrease in the
yields. Electron donating substituents at meta position on aniline
(Cl˂Me˂OMe) afforded better yields with acyclic ketones (entry
10b-d). In case of unsymmetrical ketones 9f-g, excellent
regioselectivities were observed leading to the formation of a
single isomer, among the four possible isomeric products (Table
3).
Anilines Time
Product
8 (a-i)
Yield
(%)b
Entry
(n)
6 (a-i)
(h)
a
b
c
d
e
f
g
h
i
H
20
1
8a
8b
8c
8d
8e
8f
8g
8h
8i
45
46
21
4-Me
4-Cl
4-NO2
3-OMe
3-Me
3-Cl
3-NHAc
2-OMe
2-Me
H
20
24
24
20
20
20
20
48
48
24
24
1
1
1
1
1
1
1
1
1
2
2
c
-
76
73
30
76
20
12
40
63
j
k
l
8j
8k
8l
3-OMe
a Reaction condition: aniline (5 mmol), ketone (25 mmol),
p-TSA (20 mol%), DMF (5 mL), b Isolated yields. c desired
product was not observed on TLC.
In another study to standardize the optimal equivalents of
the reactants, set of experiments were carried out varying the
equivalents of cyclopentanone. The results revealed that
employing 5 equivalents of ketone w.r.t aniline gives optimum
yield of dihydroquinoline 8a (Table 2, entry a). Having optimized
the reaction condition, attempt was made to examine the
versatility of the methodology to afford corresponding
Scheme
dihydroquinoline formation
2
Plausible mechanism of 1,2-
2 | J. Name., 2012, 00, 1-3
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We postulate the sequence of reactions as (i) ketone (11)
undergoes acid catalysed self aldol condensation to give α-β
unsaturated ketone (12), (ii) Michael addition of aniline onto α-β
unsaturated ketone to give arylamino ketone (13), (iii) followed by
intramolecular cyclisation to give hydroxy compound (14) and finally
acid catalysed dehydration to give 2,2,4-trimethyl-1,2-
dihydroquinoline (15) as depicted in scheme 2.
To find insight into the plausible mechanism, we directly
subjected mesityl oxide (17) with m-anisidine under optimized
reaction condition providing 1,2-dihydroquinoline (10b) in 50% yield.
Analytical data confirms the formation of same product as obtained
in (Table 3, entry b), when acetone reacts with m-anisidine under
optimized reaction condition, indicates that it follows the proposed
pathway.
ARTICLE
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Scheme 3 Reaction of aniline with mesityl oxide
In summary, we have developed a simple and efficient
method for the synthesis of polysubstituted 1,2-
dihydroquinoline derivatives, via one-pot tandem process
employing p-TSA as metal free catalyst. Excellent
regioselectivity
(for
meta-substituted
anilines
and
unsymmetrical ketones), good yields and wide substrate scope
are some of the salient features of our work. We do hope that
this one pot synthesis of functionalised dihydroquinolines with
concomitent generation of tetracyclic core having a quaternary
carbon centre would motivate the readers to further enhance
and explore the utility of current cascade.
12. K. Makino, O. Hara, Y. Takiguchi, T. Katano, Y. Asakawa, K.
Hatano and Y. Hamada, Tetrahedron Lett., 2003, 44, 8925.
Experimental
In a reaction vial containing a magnetic stir bar, was taken a mixture
of aniline 6a−l (1.0 equiv.), ketone, 7 or 9 (5.0 equiv.) and p-toluene
sulfonic acid (0.2 equiv.) in DMF (1 mL per mmol of substrate).
Reaction vial was capped and stirred at the specified temperature
(140°C) until complete disappearance of the starting material was
observed by TLC. The reaction was transferred to a separatory funnel
containing water and extracted with diethyl ether (3 × 30 mL). The
combined organic extracts were dried over Na2SO4, and solvent was
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (gradient elution with EtOAc and
hexanes).
Acknowledgements
We gratefully acknowledge the support from Lupin Limited.
Notes and references
1. (a) A. Balayer, T. Sevenet, H. Schaller, A. Chiaroni, C. Riche
and M. Pais, Nat. Prod. Lett.1993, 2, 61–67; (b) F. Abe, T.
Yamauchi, H. Shibuya, I. Kitagawa and M. Yamashita,
Chem. Pharm. Bull., 1998, 46, 1235–1238.
2. H. Takahash, Y. Bekkali, J. Proudfoot, G. Nabozny and D.
Thomson, Bioorg. Med. Chem. Lett., 2007, 17, 5091.
3. A. Shah, J. Pierson and S. Pavlostathisa, Water Res. 2005,
39, 4251−4263.
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Table Of Contents
Sr. No. Heading
Graphical abstract
1
Text
2
A simple, convenient and efficient metal free approach towards
the synthesis of polysubstituted 1,2-dihydroquinolines.