Facile four-component domino reactions for the synthesis of highly functionalized tetrahydroquinolones

Article abstract of DOI:10.1016/j.tetlet.2013.07.091

The four-component domino reactions of (E)-3-(dimethylamino)-1-arylprop-2- en-1-ones with anilines, aromatic aldehydes, and 1,3-cyclohexanediones in an equimolar ratio in acetic acid afforded functionalized tetrahydroquinolones in good yields. This one-pot transformation involves the formation of two C-C and two C-N bonds in a single synthetic operation.

Full text of DOI:10.1016/j.tetlet.2013.07.091

Accepted Manuscript
Facile four-component domino reactions for the synthesis of highly functional‐
ized tetrahydroquinolones
Sivasubramanian Muthusaravanan, Balasubramanian Devi Bala, Subbu
Perumal
PII:
S0040-4039(13)01250-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.091
TETL 43289
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 May 2013
15 July 2013
17 July 2013
Please cite this article as: Muthusaravanan, S., Bala, B.D., Perumal, S., Facile four-component domino reactions
for the synthesis of highly functionalized tetrahydroquinolones, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.07.091
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Facile four-component domino reactions for the synthesis of highly
functionalized tetrahydroquinolones
Sivasubramanian Muthusaravanan, Balasubramanian Devi Bala and Subbu Perumal*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai 625 021, India
Abstract: The four-component domino reactions of (E)-3-(dimethylamino)-1-arylprop-2-en-1-
ones with anilines, aromatic aldehydes and 1,3-cyclohexanediones in an equimolar ratio in acetic
acid afforded functionalized tetrahydroquinolones in good yields. This one-pot transformation
involves the formation of two C-C and two C-N bonds in a single synthetic operation.
____________________________________
Keywords: Domino reaction, four-component, (E)-3-(dimethylamino)-1-arylprop-2-en-1-one, aniline,
tetrahydroquinolinones
Corresponding author: Tel./Fax: 91-452-2459845; e-mail: subbu.perum@gmail.com
1

The quinolone moiety is an important scaffold in several biologically active natural products and
their analogues are of great importance in biochemistry and pharmaceuticals.1
Tetrahydroquinolines show a wide range of biological activities.2-4 In particular, they exhibit
anti-allergenic,2 psychotropic,5 antioxidant, anti-inflammatory,6 estrogenic,7 cerebral anti-
ischemic activity in the treatment of Alzheimer’s disease, neuroprotectant and platelet anti-
aggregatory activity, besides being useful as chemosensitizer in tumor therapy.8 Oxolinic acid,
nalidixic acid, cinoxacin and flumequine drugs possessing quinolone sub-structure are currently
employed in the treatment of gram-negative bacteria.9
Despite the above biological importance of quinolones and their derivatives, studies on their
synthesis are rather limited, which include: (i) a two-step reaction starting from anthranilic acid
via the in situ generation of 1-methyl/phenyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-
carboxylic acid methyl esters,10 (ii) two-component N-heterocyclic carbene (NHC)-catalyzed
cascade synthesis of 1-substituted 4-aryl-tetrahydroquinoline-2,5-diones from -bromocinnamic
aldehyde and 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone11 (iii) three-component synthesis
of tetrahydroquinolin-5-ones from enaminones, ammonium acetate and cyclic diketones
using heterogeneous catalyst, K5CoW12O40.3H2O12 and (iv) four-component reactions of cyclic
diketones, aromatic aldehyde, ethyl cyanoacetate or ethyl acetoacetate and ammonium acetate in
the presence of ceric ammonium acetate and metal nanoparticles such as Ni or Pd.13,14 These
methods, however, suffer from one or more disadvantages such as costly reactants/catalysts, low
or inconsistent yields, low intrinsic structural variability of the reactants etc. Consequently, we
were prompted to report in this Letter an expedient four-component approach for the synthesis of
novel 3-aroyl-1,4-diaryl-4,6,7,8-tetrahydroquinolin-5(1H)-ones in good yields (Scheme 1). This
method, endowed with high intrinsic structural variability, is amenable for a large library
synthesis. This investigation forms a part of our exploratory research embarked on the synthesis
of novel biologically relevant heterocycles employing multi-component domino/sequential/
green transformations.15 It is pertinent to note that multi-component reactions (MCRs) have
advantages such as high bond forming efficiency, convergence, operational simplicity, reduction
in waste generation and hence conform to the principles of green chemistry.
2

The enamino ketones, viz. (E)-1-(4-aryl)-3-(dimethylamino)prop-2-en-1-ones 1 required for the
present work were readily prepared by a literature method.16 We started our study by examining
the model four-component reaction of an equimolar mixture of (E)-3-(dimethylamino)-1-p-
tolylprop-2-en-1-one 1, 4-isopropylbenzaldehyde 2, 4-chloroaniline 3 and cyclohexane-1,3-dione
4 affording 5f (Table 1). Initially, the reaction was investigated in different solvents as well as
under solvent- and catalyst-free conditions (Table 1) with a view to finding optimal conditions to
maximize the yield of the product. The reaction in ethanol using various catalysts such as CAN,
p-TSA, L-proline and iodine afforded a lower yield of 5f, while the reaction in AcOH solvent,
which could also play the role of a catalyst, at reflux furnished a higher yield of the product in
short reaction time (Table 1, entry 7). The above reaction in the presence of TFA, HCOOH,
glycol in aq. acetic acid, aq. HCl and aq. H2SO4 (Table 1, entries 9-14) failed to proceed or
afforded a low yield of the product, despite allowing long reaction times. The reaction when
performed in the absence of any catalyst in DMF, ethanol and water failed to afford the product,
while the reaction in water in the presence of K-10 montmorillonite clay and p-TSA (20 mol%)
(Table 1, entries 17 and 18) diminished the yield of the product. Hence the reaction in AcOH
under reflux emerged as the ideal reaction conditions for this transformation.
With the above results in hand, the scope of the reaction was investigated under the optimal
conditions established above using (E)-3-(dimethylamino)-1-arylprop-2-en-1-ones, cyclohexane-
1,3-diones, anilines and aromatic aldehydes bearing different substituents in the aryl rings (Table
2). Typically, the reaction of an equimolar mixture of eanamino ketone 1, aromatic aldehyde 2,
aniline 3 and cyclohexane-1,3-dione 4 in AcOH (15 ml) at 120 oC for 4-6 h afforded a library of
novel 3-aroyl-1,4-diaryl-4,6,7,8-tetrahydroquinolin-5(1H)-ones 5 in good yields (73-96%; Table
2), considering the four-components involved in this reaction.17
The structure of the product 5 is in accord with combustion as well as one- and two-dimensional
NMR spectroscopic data as illustrated for a representative example 5f (vide supporting
information). A single crystal X-ray crystallographic study (Figure 3) of 5b confirms the
structure arrived at from NMR spectroscopic data.18 The X-ray structure of 5b further discloses
(i) a half chair conformation for the cyclohexenone ring and a non planar conformation for the
dihdyropyridine ring and (ii) that the N-aryl, C-aryl and C-aroyl rings are twisted out-of-plane
3

from the general plane of the dihdyropyridine ring to minimize steric interactions.
The plausible mechanistic pathway for the formation of 5 through four-component, one pot,
domino reaction is depicted in Scheme 2. Presumably, acetic acid catalyzes the formation of
arylidenecyclohexane-1,3-dione 6 from the reaction of cyclohexane-1,3-diones with aromatic
aldehyde. This intermediate
6
undergoes Michael addition with (E)-1-phenyl-3-
(phenylamino)prop-2-en-1-one 7, formed by the reaction of 1 with aniline via an addition-
elimination mechanism, leading to the formation of the Michael adduct 9 via intermediate 8.
Subsequent annulation of Michael adduct followed by dehydration affords the quinolone 5.
In conclusion, we have described a facile protocol employing domino reactions to access the
hitherto unreported tetrahydroquinolones from simple, readily available starting materials in a
one pot operation in good yields. This methodology has several advantages such as
convergence, multi-component domino protocol possessing high intrinsic variability amenable
for combinatorial synthesis employing simple starting materials affording good yields of product.
Acknowledgements
SP thanks the Department of Science Technology and the Council of Scientific and Industrial
Research, New Delhi for the award of major research projects (No. SR/S1/OC-50/2011 and No.
01(2433)/10 EMR-II). SP also thanks the University Grants Commission, New Delhi for the
award of UGC-BSR Faculty Fellowship.
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4

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5

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Res. Synop. 1999, 654-655.
17. General procedure for the synthesis of tetrahydroquinolinones 5
An equimolar mixture of (E)-1-(4-aryl)-3-(dimethylamino)prop-2-en-1-one 1 (1 mmol), 1,3-
diketone (1 mmol), aniline (1 mmol) and aromatic aldehyde (1 mmol) in acetic acid (15 ml)
was heated at 120 °C for 4-6 h. The reaction progress was monitored by thin layer
chromatography. After completion of the reaction, the solvent was removed and the product was
purified by flash column chromatography on silica gel using petroleum ether–ethyl acetate
mixture (4:1 v/v) as eluent to obtain pure tetrahydroquinolinones 5.
Analytical data for a few representative tetrahydroquinolinones 5 are given below.
1-(4-chlorophenyl)-4-(4-isopropylphenyl)-3-(4-methylbenzoyl)-4,6,7,8-tetrahydroquinolin-
5(1H)-one 5f
1
Isolated as pale yellow solid Yield :73% m.p.=220 ºC H NMR (300 MHz, CDCl3) δH 1.20 (d,
6H, J = 6.9 Hz), 1.86-1.98 (m, 2H), 2.09-2.20 (m, 1H), 2.26-2.44 (m, 3H), 2.33 (s, 3H), 2.78-
2.87 (m, 1H), 5.48 (s, 1H), 6.97 (s, 1H), 7.09-7.14 (m, 4H), 7.22-7.23 (m, 2H), 7.33 (d, 2H, J =
13
8.1 Hz), 7.40 (d, 2H, J = 7.8 Hz), 7.44 (d, 2H, J = 8.7 Hz) C NMR (75 MHz, CDCl3) δc 21.3,
21.4, 23.9, 27.4, 33.6, 34.4, 36.9, 115.9, 119.7, 126.4, 127.6, 128.1, 128.6, 128.8, 130.2, 134.7,
136.3, 140.3, 141.2, 141.4, 143.2, 146.5, 150.1, 194.2, 195.7 Anal. Calcd for C32H30ClNO2 C,
77.48; H, 6.10; N, 2.82% found C, 77.57; H, 6.01; N, 2.75%
3-(4-chlorobenzoyl)-4-(4-isopropylphenyl)-1-(4-methoxyphenyl)-7,7-dimethyl-4,6,7,8-
tetrahydroquinolin-5(1H)-one 5k
1
Isolated as yellow gummy solid. Yield :93% H NMR (300 MHz, CDCl3) δH 0.91 (s, 3H), 0.98
(s, 3H), 1.19 (d, 6H, J = 6.9 Hz), 2.99-2.15 (m, 2H), 2.21 (s, 2H), 2.81-2.85 (m, 1H), 3.86 (s,
6

3H), 5.42 (s, 1H), 6.93- 6.99 (m, 3H), 7.09-7.18 (m, 4H), 7.30-7.35 (m, 4H), 7.40-7.42 (m, 2H)
13C NMR (75 MHz, CDCl3) δc 23.9, 27.4, 29.0, 32.5, 33.6, 34.5, 40.7, 50.4, 55.5, 114.5, 115.2,
118.9, 126.3, 127.6, 128.3, 128.5, 129.8, 134.3, 136.8, 137.6, 142.8, 143.2, 146.5, 149.2, 159.7,
193.1, 195.6 Anal. Calcd for C34H34ClNO3 C, 75.61; H, 6.35; N, 2.59 % Found C, 75.68; H,
6.44; N, 2.51 %
3-benzoyl-7,7-dimethyl-4-(4-nitrophenyl)-1-p-tolyl-4,6,7,8-tetrahydroquinolin-5(1H)-one 5n
1
Isolated as pale yellow gummy solid. Yield: 89% H NMR (300 MHz, CDCl3) δH 0.85 (s, 3H),
0.96 (s, 3H), 2.01-2.12 (m, 2H), 2.15-2.25 (m, 2H), 2.39 (s, 3H), 5.52 (s, 1H), 7.06- 7.12 (m,
3H), 7.23-7.32 (m, 4H), 7.36-7.43 (m, 2H), 7.60-7.63 (m, 2H), 8.10-8.13 (m, 2H) 13C NMR (75
MHz, CDCl3) δc 21.1, 27.2, 29.1, 32.6, 35.7, 40.7, 50.3, 113.4, 117.5, 123.6, 127.0, 128.3, 128.3,
128.9, 130.9, 131.1, 138.7, 139.4, 143.6, 146.4, 149.9, 153.3, 193.9, 195.6. Anal. Calcd for
C31H28N2O4 C, 75.59; H, 5.73; N, 5.69 % Found C, 75.66; H, 5.68; N, 5.61%
18. Crystallographic data (excluding structure factors) for 3-benzoyl-1-(4-methoxyphenyl)-4-p-
tolyl-4,6,7,8-tetrahydroquinolin-5(1H)-one 5b in this Letter have been deposited with Cambridge
Crystallographic Data Centre as supplementary publication number CCDC 941193 Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
7

Scheme 1. Synthesis of functionalized tetrahydroquinolinones 5
8

Table 1 Optimization of reaction conditions for
the preparation of compound 5f
Entry Solvent
Catalyst (mol%) Temp. Time Yield
(oC)
120
(h.)
5
(%)a
b
1
Solvent-
free
-
-
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
EtOH
EtOH
EtOH
EtOH
L-proline (20)
CAN (20)
p-TSA (20)
Iodine (20)
-
-
AcOH (20)
-
-
-
-
-
-
-
80
80
80
80
12
12
12
12
10
6
10
12
8
68
42
48
44
b
EtOH
80
-
HOAc
DMF
120
120
110
110
110
110
123
120
120
100
100
73
46
56
aq. HOAcc
d
b
aq. H2SO4
aq. HCle
TFA
HCOOH
Glycol
DMF
-
b
8
-
10
10
10
10
6
44
32
10
b
-
b
Water
Water
-
-
K-10
12
37
Montmorillonitef
p-TSA (20)
18
Water
100
12
65
a Yield calculated from crude NMR spectrum, conversion based on starting material
b
to product; No reaction occurred; c HOAc (17 mmol in 3 ml);
d H2SO4 (5 mmol in 2.5 ml); e HCl (12 mmol in 3 ml); 20 mg of K-10 Montmo-
rillonite in equimolar amount (1 mmol) of reactants
9

Table 2. Synthesis of functionalized tetrahydroquinolin-5(1H)-ones 5
5c (94%)
5d (84%)
5b (88%)
5a (92%)
5g (84%)
5h (82%)
5e (78%)
5f (73%)
5i (85%)
5j (91%)
5k (93%)
5l (90%)
Table 1 continued
10

5p (85%)
5o (88%)
5n (89%)
5m (93%)
a Yield after filtration through a pad of silica gel.
11

Figure 1. ORTEP diagram of 5b
12

Scheme 2. Plausible mechanism for the formation of functionalized tetrahydroquinolinones 5
13

Graphical abstract
Facile four-component domino reactions for the synthesis of highly
functionalized tetrahydroquinolones
Sivasubramanian Muthusaravanan, Balasubramanian Devi Bala and Subbu Perumal*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai 625 021, India
14

Graphical abstract
Facile four-component domino reactions for the synthesis of
highly functionalized tetrahydroquinolones
Sivasubramanian Muthusaravanan, Balasubramanian Devi Bala and Subbu Perumal*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai 625 021, India