Water mediated catalyst-free efficient domino synthesis of 9-(quinolin-2(1H)-one)-xanthene-1,8(5H,9H)-diones using parallel synthesizer

Article abstract of DOI:10.1016/j.tetlet.2014.05.015

A facile and efficient method for the preparation of 3,4,6,7-tetrahydro-9- (1,2-dihydro-2-oxoquinolin-3-yl)-2H-xanthene-1,8(5H,9H)-diones from substituted 2-chloro-3-formylquinoline and 1,3-cyclohexanedione or dimedone in water at 90 °C using parallel synthesizer is reported. The present methodology offers a tandem-cascade methodology, high yield, and operational simplicity.

Full text of DOI:10.1016/j.tetlet.2014.05.015

Accepted Manuscript
Water mediated catalyst-free efficient domino synthesis of 9-(quinolin-2(1H)-
one)-xanthene-1,8(5H,9H)-dionederivatives using parallel synthesizer
Varadhan Krishnakumar, Badal Kumar Mandal, Fazlur- Rahman Nawaz Khan,
Euh Duck Jeong
PII:
S0040-4039(14)00793-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.015
TETL 44606
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 February 2014
3 May 2014
7 May 2014
Please cite this article as: Krishnakumar, V., Mandal, B.K., Khan, F.R., Jeong, E.D., Water mediated catalyst-free
efficient domino synthesis of 9-(quinolin-2(1H)-one)-xanthene-1,8(5H,9H)-dionederivatives using parallel
synthesizer, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.015
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GRAPHICAL ABSTRACT
Water mediated catalyst-free efficient domino synthesis of 9-(quinolin-2(1H)-
one)-xanthene-1,8(5H,9H)-dione derivatives using parallel synthesizer
1

Water mediated catalyst-free efficient domino synthesis of 9-(quinolin-2(1H)-
one)-xanthene-1,8(5H,9H)-dionederivatives using parallel synthesizer
Varadhan Krishnakumara,b, Badal Kumar Mandalb*, Fazlur- Rahman Nawaz
Khana*, Euh Duck Jeongc*,
aOrganic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT-University, Vellore 632 014, Tamil Nadu, India.
bTrace Elements Speciation Research Laboratory,Environmental and Analytical Chemistry
Division,School of Advanced Sciences, VIT-University, Vellore 632 014, Tamil Nadu, India.
cKorea Basic Science Institute, Busan Center, Busan 618 230, South Korea
*Correspondence: E-mail; Prof. F. Nawaz Khan: nawaz_f@yahoo.co.in
Prof. B. K. Mandal: mbadal@hotmail.com; Dr ED Jeong, edjeong@kbsi.re.kr
Abstract:
A facile and efficient method for the preparation of 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-
oxoquinolin-3-yl)-2H-xanthene-1,8(5H,9H)-diones from substituted 2-chloro-3-formylquinoline
o
and 1,3-cyclohexanedione or dimedone in water at 90 C using parallel synthesizer is reported.
The present methodology offers a tandem-cascade methodology, high yield and operational
simplicity.
Keywords: Aqueous media, Domino reaction, 2-Quinolones, Xanthene-1,8-diones
2

Utilization of organic solvents in an industrial scale leads to environmental pollution and causes
many diseases and severe problems.1 In this context, promising solvent media like glycerol,2
polyethylene glycol,3 ionic liquids4,5 and supercritical fluids6 have been utilized to overcome the
above drawbacks. However, use of these solvents has limitations such as high cost, toxicity,7
need of high purity8,9 and biodegradability.10 In recent years, microwave irradiation,13
ultrasonication14 and ball milling15 methods are used for many organic transformations to afford
the desired products in shorter time and high yield. These methods are generally expensive and
involve organic solvents to carry out the reactions and isolation of the products and are not
convenient for largescale.16,17
Water is an ideal solvent in organic reactions,18-20 that offers many advantages. Similarly,
cascade-tandem reactions involve consecutive sequence of transformations through highly
reactive intermediates produced in situ.21,22 Motivated by the above facts the present work
envisioned the design of green chemical approach involving water mediated domino reaction in
efficient synthesis of the target molecule, xanthene-1,8-diones under catalyst-free conditions.
Quinolones and xanthene-1,8-diones display wide range of applications in medicinal and
pharmaceutical industries.23-30 Xanthenes and their analogues are also known to exhibit a broad
range of biological activities and pharmaceutical properties (e.g.) antimicrobial,31 antioxidant,32
antimalarial,33 anti-inflammatory34 and anticancer.35 They were also used in dyes and pigments36
and as luminescent sensors.37
In our continued C-C bond formation research interests,38-47 preliminary reaction between 2-
chloro-3-formylquinoline (1) and dimedone (2) in ethanol under reflux condition was
investigated in the absence of catalyst. Surprisingly, the reaction proceeded smoothly in the
absence of catalyst to offer an unexpected product confirmed by different spectral techniques.
3

Based on spectral data the compound was identified as 3,3,6,6-tetramethyl-9-(2-oxo-1,2-
dihydroquinolin-3-yl)-3,4,6,7-tetrahydro-2H-xanthene-1,8(5H,9H)-dione (Scheme 1).
R1
N
Cl
O
O
R2 R2
expected
R2
R2
CHO
Cl
H2O
R2
R2
R1
90 oC
O
O
O
N
2 (a,b)
1 (a-f)
H2O
90 oC
R1
NH
O
O
O
R2 = H, CH3
R1= H, 6-CH3, 7-CH3, 8-CH3, 6-OCH3, 7,8-diCH3
R2
R2
R2
R2
O
3 (a-r)
Scheme 1.Synthesis of 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-oxoquinolin-3-yl)-2H-xanthene-
1,8 (5H,9H)-dione
With this observation, optimization of catalyst, solvent and temperature was investigated
utilizing the parallel synthesizer to improve the product yield. In the presence of p-TSA
(paratoluenesulfonic acid) or MK-10 (Montmorillonite K-10), the same product 3 was formed,
(Table 1, entry 3 and 4). For this reaction, water was found to be the best, (Table 1). In the
literature, 2-chloro-3-formylquinoline has been shown to react with sarcosine in refluxing
xylene to afford 2-methyl-5,9b-dihydro-1H-pyrrolo[3,4-c]quinolin-4(2H)-ones in moderate
yield.48 In the present study, we find that water was responsible for the hydrolysis of halide under
the reaction conditions to offer the oxoderivative, 3.
4

Table 1. Optimization of solventa
Yield (%)b
Entry
Solvent
Methanol
1
2
3
4
5
6
7
66
74
76
74
72
70
85
Ethanol
Ethanol/pTSA
Ethanol/MK-10
Isopropanol
n-Butanol
Water
a2-Chloro-3-formylquinolines (1 mmol), dimedone (2 mmol),
5 mL of appropriate solvent under reflux; bisolated yield.
Then, we varied the temperature to improve product yield. The reaction doesn’t proceed with
water at room temperature. However, when the temperature was maintained between 50 and 90
oC, the product yield increased, (Table 2, entry 8).
Table 2: Effect of temperaturea
Entry
Temperature (oC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
RT
50
60
70
75
80
85
90
24
24
12
12
12
5
No reaction
Traces
38
40
45
65
4
73
2
85
a2-Chloro-3-formylquinolines (1mmol), dimedone (2mmol), 5 mL of water; bisolated yield.
5

With these optimized results in hand49, the scope of reaction was investigated using substituted
2-chloro-3-formylquinolines, dimedone or 1,3-cyclohexanedione.
Table 3: Synthesis of 9-(quinolin-2(1H)-one)-xanthene-1,8(5H,9H)-dionederivativesa
NH
NH
NH
NH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3a, 2.5h, 86%
3b, 4h, 65%
3c, 2h, 76%
3d, 2.5h, 82%
O
NH
NH
NH
NH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3g, 2h, 85%
3h, 3.5h, 75%
3e, 2h, 86%
3f, 3h, 75%
O
NH
O
NH
NH
NH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3l, 3h, 78%
3j, 2h, 82%
3i, 2h, 80%
3k, 1.5h, 84%
a2-Chloro-3-formylquinolines (1mmol), cyclohexane-1,3-dione or dimedone (2mmol),
5 mL of water, reaction temperature 90 oC, bisolated yield.
It was observed that all the aldehydes reacted with dimedone or 1,3-cyclohexanedione to furnish
symmetrical xanthenes-1,8-diones in good yield in aqueous media.
With these results in hand, substituted 2-chloro-3-formylquinolines, 1,3-cyclohexanedione and
dimedone were reacted in the same reaction flask to obtain the desired unsymmetrical
6

3,4,6,7-tetrahydro-9-(1,2-dihydro-2-oxoquinolin-3-yl)-3,3-dimethyl-2H-xanthene-1,8(5H,9H)-
dione derivatives, (Table 4). All the starting materials taken in equal mole ratio in water at 90 oC
afforded the desired unsymmetrical xanthenedione products.
Table 4: Synthesis of 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-oxoquinolin-3-yl)-3,3-
dimethyl-2H-xanthene-1,8(5H,9H)-dione derivativesa
NH
NH
NH
O
O
O
O
O
O
O
O
O
O
O
O
3m, 5h, 75%
3n, 6h, 60%
3o, 4.5h, 72%
O
NH
NH
NH
O
O
O
O
O
O
O
O
O
O
O
O
3q, 5h, 80%
3p, 5h, 77%
3r, 5.5h, 72%
a2-Chloro-3-formylquinolines (1mmol), cyclohexane-1,3-dione (1mmol) and
dimedone (1mmol), 5 mL of water, reaction temperature 90 oC, bisolated yield.
Among the differently substituted 2-chloro-3-formylquinoline all the derivatives gave good
yields of product in shorter reaction time but the 8 and 7,8-disubstitutions considerably required
longer reaction time due to the interaction between the 8-methyl and NH group (see supporting
documents).
In the 13C NMR spectra, the peaks for carbonyl carbon (C=O) appeared at δ197.19-197.51 and
the peaks for amide carbonyl (NH-C=O) appears at δ 164.69-166.37 which confirms the
formation of the title compound (see Supporting Information, SI). For compound 3g the DEPT-
135 spectrum shows the aromatic C-H carbons at δ 141.12, 129.43, 128.61, 122.12, 114.88
7

methyne (CH) C-9 proton at 31.23 and methyl (CH3) groups at δ 29.34, 27.00 in the up peaks.
Methylene group (CH2) shows at 50.91 and 41.01 in the down peaks (see Figure 1, SI). HRMS
spectrum of the compound 3g (m/z 417. 1936) matches with the molecular weight (m/z 417.
1940)of the compound. All the above data confirm the formation of product 3 (a-r) (see SI).
A possible mechanism for the domino synthesis of 9-(quinolin-2(1H)-one)-xanthene-
1,8(5H,9H)-dione was given in Scheme 2. Initially, 2-chloro-3-formylquinoline gets hydrolyzed
to give 2-oxo-3-formylquinoline 1i (see Figure 2a & 2b in the SI). First molecule of 1,3-
cyclohexanedione condenses with 2-oxo-3-formylquinoline. Further, the active methylene group
of second 1,3-cyclohexanedione molecule react with intermediate 2i through Michael addition to
give the intermediate 3i, which further undergoes intra-molecular cyclodehydration to furnished
the 9-(quinolin-2(1H)-one)-xanthene-1,8(5H,9H)-dione.
To understand the mechanism of the reaction, we checked the pH of the dimedone and
1,3-cyclohexanedione in water and it was weakly acidic (pH = 5). We assume this weakly
acidic medium facilitates and hydrolysis of the chlorine to hydroxyl functional group in the 2-
chloro-3-formylquinoline.
8

Scheme 2: Plausible mechanism for the formation of xanthene-1,8-dione
H+
O
O
N
Cl
N
H
Cl
H
H
O
1
O
H
O
N
H
HN
Cl
O
1i
O
O
O
H
H
O
O
3
H
N
O
O
H
H
-H2O
O
O
O
2
1i
HN
H
O
O
O
OH
O
O
-H2O
O
H
O
O
O
O
3i
HN
2i
In conclusion, an efficient chemical approach for the synthesis of 9-(quinolin-2(1H)-one)-
xanthene-1,8(5H,9H)-dione derivatives in aqueous medium has been established. The catalyst-
free cascade-tandem reaction provides high yield of heterocyclic framework of 9-(2-
quinolo)xanthene-1,8-diones 3 (a-r). The current protocol offers a convenient procedure in one-
pot to give high yield of products utilizing available starting materials.
Acknowledgements The authors thank VIT University for providing laboratory facilities. We
acknowledge the help of SIF-VIT for providing the NMR facilities (supported by DST-FIST)
and IITM, Chennai for providing HRMS analysis.
9

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49. General procedure for the synthesis of 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-
oxoquinolin-3-yl)-2H-xanthene-1,8(5H,9H)-dione
In a typical procedure, a mixture of 2-chloro-3-formylquinoline (1.0 mmol), 1,3-
cyclohexanedione (2.0 mmol), distilled water (5.0 mL) was taken in 20 mL reaction vial and kept
in parallel synthesizer then heated at 90 oC. Progress of the reaction was monitored by thin layer
chromatography. After completion of reaction, the product was filtered and washed with water.
The obtained compound was pure enough for further analysis.
12